UA82196C2 - Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds - Google Patents

Abstract

The present invention provides methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds, as well as methods of treating, preventing or ameliorating symptoms associated with such diseases. Specific examples of autoimmune diseases that can be treated or prevented with the compounds include rheumatoid arthritis and/or its associated symptoms, systematic lups erythematosis and/or its associated symptoms and multiple sclerosis and/or its associated symptoms.

Description

Description of the invention

Pursuant to 35 USC § 5119(e) (Appendix 0.5.S.), the valid application has priority 9 to the following applications: Registration No. 60/399,673, filed July 29, 2002; registration number 60/443,949, filed on January 31, 2003 and registration number 60/452,339, filed on March 6, 2003.

The present invention relates mainly to 2,4-pyrimidinediamine compounds, pharmaceutical compositions containing the specified compounds, intermediate compounds, synthetic methods for the production of these compounds and methods of using these compounds and compositions in various fields, for example, in the treatment or prevention of autoimmune diseases and /or symptoms associated with them.

Cross-linking of Es receptors, such as the high-affinity receptor for IDE (Bs is CI) and/or the high-affinity receptor for dos (Esu CI), activates a signaling cascade in mast cells, basophils and other immune cells that leads to the release of chemical messengers, responsible for many adverse events. For example, such cross-linking leads to the release of pre-formed mediators of anaphylactic hypersensitivity reactions of the type | (immediate type hypersensitivity reactions) such as histamine from granule storage via degranulation. It also leads to the synthesis and release of other mediators, including leukotrienes, prostaglandins, and platelet-activating factors (PAFs), which play an important role in the course of inflammatory responses. Additional mediators synthesized and released as a result of cross-linking of 20 E receptors include cytokines and nitric oxide.

Signaling cascade or cascades activated as a result of cross-linking of Es receptors, such as Es KI and/or Es

CI contains a set of cellular proteins. The most important intercellular signal multipliers are tyrosine kinases. Zuk kinase is an important tyrosine kinase involved in signal transduction pathways associated with cross-linking of Ese KI and/or Ese KI receptors, as well as other signal transduction cascades, see Maiepi egai., 2002, Ipid. U. Netayo!. 75 (4): 257-362). at

Since the mediators released as a result of the cross-linking of Esu KI and Esu KI receptors are responsible for or play an important role in the manifestation of numerous adverse events, it is highly desirable to have compounds capable of inhibiting the signaling cascade(s) that initiate their release. Moreover, due to the critical role that Zuk kinases play in the signaling cascade of these and other receptors, the presence of compounds capable of inhibiting Zuk kinase would also be desirable. (at)

One of the aspects of this invention is the proposal of new compounds of 2,4-pyrimidinediamine, which, as will be more detailed below, show biological activity in a number of directions. In general, these compounds contain a 2,4-pyrimidinediamine "rod" that has the following structure and numbering system: NM TM MN 2 2

With so io) Compounds according to the present invention are substituted in the place of attachment of nitrogen (M2) to the C2 atom with the aim of forming a secondary amine and can optionally be substituted in one or more positions: in the 5-position of attachment of nitrogen (M4) to C4 atoms, C5 and/or Sat. When substituted at the M4 position, the substituent forms a secondary (se) amine. The substituent in the M2 node, as well as the substituents in other positions, can vary widely in their own

Fo characteristics and physical and chemical properties. For example, the substituent(s) may be branched, unbranched or cyclic alkyl, branched, unbranched or cyclic heteroalkyl, mono- or polycyclic aryl, mono- or polycyclic heteroaryl, or combinations of these groups. These substitution groups

Can be further replaced, as will be described in more detail below.

Substituents M2 and/or M4 can be attached directly to the corresponding nitrogen atoms or separated

HF) from the corresponding nitrogen atoms with the help of linkers, which can be the same or different. The nature of the linkers can be diverse and can include almost any combination of atoms or groups suitable for distancing one part of the molecule from another. For example, the linker can be an acyclic hydrocarbon bridge boron, for example, a saturated or unsaturated alkylene-, such as methane-, ethane-, ethene-, propane-, propylene-, butane-, butylene-, butylene-, buta(| 1,3|diene-, and similar), monocyclic or polycyclic hydrocarbon bridge

And for example, (|1,2| benzene-, |2,3| naphthalene-, and the like), a simple ordinary acyclic heteroatomic or heteroalkyldiyl bridge "for example, -O-, -5-, -5-0-, -МН- . 0-СНо-, -СН, -0-СНо-, -0-СНАСН-СНо-, and the like), monocyclic or polycyclic 65 heteroaryl bridge (for example, 3,4|furan-, pyridine-, thiophene-, piperidine- , piperazine-, pyrazidin-, pyrrolidine-, and the like) or combinations of such bridges.

Substituents in positions M2, M4, C5 and/or Cb, as well as potential linkers, can be further replaced by one or more identical or different groups of substituents. The nature of these substitution groups can be varied. Non-limiting examples of suitable substituent groups include branched, unbranched or cyclic alkyl, mono- or polycyclic aryl, branched, unbranched or cyclic heteroalkyl, mono- or polycyclic heteroaryl, halohydrocarbon, branched, unbranched or cyclic haloalkyl, hydroxyl, oxote, thioxote, branched, unbranched or cyclic olefins, branched, unbranched or cyclic haloido-alkoxys, trifluoromethoxyls, mono- or polycyclic aryloxyls, mono- or polycyclic heteroaryloxyls, ethers, alcohols, sulfides, thioethers, sulfonyls (thiols), imines, azodes, azides, amines 70 (primary , secondary and tertiary), nitriles (any isomers), cyanates (any isomers), thiocyanates (any isomers), nitroso groups, nitro groups, diazes, sulfoxides, sulfonyls, sulfonic acids, sulfamides, sulfonamides , sulfamic acid esters, aldehydes, ketones, carboxylic acids, esters, amides, amidines, formadines, amino acids, acetylenes, carbamates, lactones, lactams, glucosides, gluconorides, sulfones, ketals, acetals, thioketals, oximes, oxamic acids, oxamic acid esters, etc., and combinations of these groups. Functionally reactive substituent groups can be protected or unprotected as is well known in the art.

WITH

In one of the illustrative examples, compounds of 2,4-pyrimidinediamines according to the present invention are compounds having the following structural formula (1): b

Kk 5 s that Kk and M (o) 2 r 4 in Sun, AK 2 F with Kk M M Kk Kk F

Н НН - including their salts, hydrates, solvates and M-oxides, where: se structural links I" and I? each, independently of each other, are selected from the group containing a direct connection of ко and a linker;

IN? is selected from the group containing (C1-C6) alkyl, arbitrarily substituted by one or more identical or different KZ groups, (C3-C8) cycloalkyl, arbitrarily substituted by one or more identical or different " groups 8, cyclohexyl, arbitrarily substituted by one or more by the same or different groups in, 3-8-membered cycloheteroalkyl, arbitrarily substituted by one or several identical or different groups 8, si c (C5-C15) aryl, arbitrarily substituted by one or several identical or different groups KZ, phenyl, :z» arbitrarily substituted by one or more identical or different groups KZ and 5-15-membered heteroaryl, arbitrarily substituted by one or more identical or different groups in; 7 is selected from the group containing hydrogen, (C1-Cb) alkyl, arbitrarily substituted by one or more identical or different P groups, (C3-C8) cycloalkyl, arbitrarily substituted by one or more identical or different groups 8, cyclohexyl, arbitrarily substituted by one or several identical or different groups 8, 3-8-membered cycloheteroalkyl, arbitrarily substituted by one or several identical or different KZ groups, (C5-C15) aryl, arbitrarily substituted by one or several identical or different groups KZ, se 50 phenyl, arbitrarily substituted by one or several identical or different groups of KZ and 5-15-membered heteroaryl, arbitrarily substituted by one or several identical or different groups 8;

Shi vo is selected from the group containing vo, (C1-C6) alkyl, arbitrarily substituted by one or more identical or different B8 groups, (C1-C4) alkanyl, arbitrarily substituted by one or several identical or different KZ groups, (C2- C4) alkenyl, arbitrarily substituted by one or several identical or different KZ groups and (C2-C4) alkynyl, arbitrarily substituted by one or several identical or different groups 8; o Each 29 is independently selected from the group consisting of hydrogen, electronegative group, -OK 4 588, ko (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, -MEOKO, halogen, (C1-C3) haloidoalkyl, (C1 -C3) in perhaloidoalkyl, -SEz, -СНоСЕз, -"SEOSE", -SM, -MS, -OSM, -VSM, -MO, -MO", -M3, -(O)89, -5(0289, -(020O8, -OoMeeve; -(02D MeV, -ov(OvVU, -o8(0)589, -0O8(02089, -OoB(OMAVU, -O5(O2Me Ve, -С(ОВУ, -С(FOОv, -С(О)Meove, -С(MNIMAsVU, -ОС(0ОВ9, -всС(089У, -осС(0ОвУ, -8сС(0)0в9, -ОС(ОМесве, -8С(OMAV, -Os(Mn)Me евг, -всС(МнН)М ев, «ИМНе(ОоДВУ, Мне, -ИМНе(ОоДвМв еВ and -(ИМНО(МНЙМеУВ, (С5-С10)) aryl, arbitrarily substituted by one or more identical or different groups 8, phenyl, arbitrarily 65 substituted by one or several identical or different KU groups, (C6-C16) arylalkyl, arbitrarily substituted by one or several identical or different KZ groups, 5-10-membered heteroaryl, arbitrarily substituted by one or several identical or different K groups and 6 -16-membered heteroaryl lkilu, arbitrarily replaced by one or several identical or different groups ee

BZ is selected from the group consisting of B 2, E, K2, substituted by one or several identical or different K2 or K?, -OK2, replaced by one or several identical or different KU or K?, -B(OK2)", - В(MeУВ2)5, "(СНо)т-в?, "СНУ, -О-(СНо)т-во, -8-(СНо)т в", -0-СНВев?, -о-сКУвУ, - О-(СНе)-е, -0-(СнНозСН(СН оз ЗЕ, -8-(СНЕ2)-Б, -СШЦС(ОМН-(СНо)т-ве, -СК(ОМнА(СНАг) АК, -О -(CH) n C(OMNA(СНО) ве, -5-(СНо)т-С(ОМН-(СНо)т-в, -О-(СН2)н-С(OMNA(СНЕ )й-в, 70. -МН-С(0)-МН-(СН 2)т-ве, -МН-С(О)-(СНо)т-СНА В» and -МНА(СНо)т-С(0)-МН-( SN o)t-v;

Each KU is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl , benzyl, 2-6-ene heteroalkyl, 3-8-ene cycloheteroalkyl, morpholine, piperazinyl, homopiperazinyl, piperidinyl, 75 4-11-ene cycloheteroalkylalkyl, 5-10-ene heteroaryl and 6-16-h- linoleic heteroarylalkyl;

Every VE? is a suitable group independently selected from the group consisting of 50, -OBB 9, (C1-C3) haloidoalkyloxy, -OSEz, -5, -589, - MKU, "MOU, -MAUB2, halogen, -SEz, - SM, -MS, -OSM, -ZSM, -MO, -MO», Mo», -Maz, -(OKU9, -8(0)589, -(0)50К9, -(ООМ В, -5(0 )-Mv 22, -ОВ(О)КУ, -О05(0289, -0О5(0)20О89, -О5(О)DM В, -бОвВУ, -с(0)ок9У, -с(о)мвевВе, - s(MnuMeUvU, -s(mveMASve, -cS(MOone, -S(MonIMvevVe, -os(OvU, 2 -os(0Ov9, -oOS(OMAsVe, -«OS(IMNMAsVe, -oOS(MCMesve, "Mne U, -mvas(olvU, -MNesdovkae, -mves(OolOvU, "MNe(olMme ve, "IiMvasS(OoDMeeve, IMNS(MNUUMe V: and (mV S(Me MA Ve;

Every KE? independently represents a protecting group or KU, or, alternatively, each K- is taken together with the nitrogen atom to which it is bound to form a 5-8 membered cycloheteroalkyl or heteroaryl, which

May include one or more of the same or different additional heteroatoms and may be substituted by one or more of the same or different K2 or suitable BC groups; o each IVF independently represents a protective group or short-term care; each t represents an independent integer from 1 to 3; and each n represents an independent integer from 0 to 3. (Se)

In another aspect, the present invention provides prodrugs of 2,4-pyrimidinediamine compounds. Such prodrugs could be active in their prodrug form, or inactive until they are converted into an active drug form under physiological or other conditions of use. In the prodrugs of the present invention, one or more functional groups of 2,4-pyrimidinediamine compounds are incorporated into pro-components (rhotoyls) that are separated from the molecule under the conditions of use, typically by hydrolysis, enzymatic cleavage, or some other cleavage mechanism to form functional groups. For example, primary or secondary amino groups can be included in the amide procomponent, which is cleaved under the conditions of use, forming a primary or secondary amino group. Thus, the prodrugs according to the present invention include special types of protective groups called "progroups" and mask one or more functional groups of "2,4-pyrimidinediamine compounds that are cleaved under the conditions of use to form active medicinal compounds of 2,4-pyrimidinediamine . Functional groups included in the composition of 2,4-pyrimidinediamine compounds, which can be masked with progroups for inclusion in the procomponent, include, but are not limited to, amines (primary and secondary), hydroxyls, sulfonyls (thiols), carboxyls , are" carbonyls, phenols, catechols, diols, alkynes, phosphates, etc. Currently, many progroups are known, suitable for masking the specified functional groups in order to form procomponents capable of cleavage under the conditions of use. All of these progroups, independently or in combination, may be included in the prodrugs of the present invention. Specific examples of procomponents forming primary or secondary amino groups that may be included in the prodrugs of the present invention include, but are not limited to, amides, carbamates, imines, ureas, phosphenyls, phosphoryls, and sulfenyls. Specific examples of procomponents that form sulfonyl groups and that can be included in prodrugs according to the present invention include, but are not limited to, thioethers, for example, 5-methyl derivatives (monothio-, dithio-, oxythio-, n-o aminothio- acetals), silyl thioethers, complex thioethers, thiocarbonates, thiocarbomates, asymmetric disulfides,

I" etc. Specific examples of procomponents that are cleaved to form hydroxyl groups and that may be included in the prodrugs of the present invention include, but are not limited to, sulfonates, esters, and carbonates. Specific examples of procomponents that form carboxyl groups and may be included in the prodrugs of the present invention include, but are not limited to, esters (including silyl esters, oxamic acid esters, and thioesters), amides, and hydrazides. i) In one of the illustrative examples, prodrugs according to the present invention are compounds with the structural formula (I), in which the protective groups B: and KU are progroups.

Substitution of hydrogen atoms attached to M2 and M4 in 2,4-pyrimidinediamines, which correspond to the structural formula (I), by substituents, adversely affects the activity of the compounds. But, as experts will appreciate, these nitrogen atoms can be included in the procomponents, which under the conditions of use are split and form 2,4-pyrimidinediamines according to the structural formula (I). Thus, in another illustrative example, prodrugs according to the present invention are compounds with structural formula (11): b5

IS? at 47 Her. shu r pc | - 2

E and M X Kk

Also including their salts, hydrates, solvates and M-oxides, where: 2, you, 5, 8517 and 12 - pre-defined for structural formula (1); and 225 and E5, each independently representing a progroup.

Another aspect of the present invention is to provide compositions that contain one or more compounds and/or prodrugs of the present invention, as well as a suitable carrier, excipient or diluent. The exact nature of the carrier, excipient, or diluent will depend on the desired use of such a composition, from veterinary to human applications.

Another aspect of the present invention is to provide intermediates useful for the synthesis of 2,4-pyrimidinediamines and prodrugs of the present invention. In one of the examples, intermediate compounds are represented by C in the form of 4-pyrimidinamines with the structural formula (11): o 5 (se);

Kk de F sch 4 y s

Кк х M also including their salts, hydrates, solvates and M-oxides, where В", В, КЗ and 12 - represent the groups described earlier in the determination of the structural formula (I); ЙО represents a substitution group, such as - 5(0)2Me, -"ZMe or a halide group ц I, for example, PE, SI, Bg, |); and B: represents hydrogen or a progroup. ," In another example, the intermediate compounds are 2-pyrimidinamines that correspond to the structural formula ( IM): what so KO: yu che

ME n -y : tk h dat

R Mesa you. ia shchi o yiv V b : Z g s-y tsa ren" oo kas p ia Tl

Го) ФО 60 including their salts, hydrates, solvates and M-oxides, where 2, 5, 5 and!" are predefined for the structural formula (I); ГО represents a substitution group, such as -5(0) Me, - 5Me or a halide group (for example, PE, SI, Vg,

I) and 222 represents hydrogen or a progroup.

In another example, intermediate compounds are 4-amino- or 4-hydroxy-2-pyrimidinamines according to the structural formula (M): b5 es; io; ,F mA X

I' in BUE re M - and i p2 rgs including their salts, hydrates, solvates and M-oxides, where 2, 5, 5 and" are predetermined for the structural formula (I), B" represents an amine or hydroxyl group, and B 22 represents hydrogen or a progroup.

In another example, the intermediates are M4-substituted cytosines according to the structural formula (MI): ro ro

Mn cm o

Kk o s F "-- including their salts, hydrates, solvates and M-oxides, where 27, 8", 25 and I? defined earlier for the structural formula (I) and B" represents hydrogen or a progroup.

In yet another aspect, the present invention provides methods for the synthesis of 2,4-pyrimidinediamine compounds and prodrugs of the present invention. In one example, the indicated method involves the reaction of 4-pyrimidinamine of structural formula (I) with an amine of formula НЕ22М-И1-К2, where I", КК? and BK? are defined above for structural formula (IM) in order to form 2.4 -pyrimidinediamine with the structural formula (I), or prodrugs with the structural formula (I). З7З c In another example, the indicated method involves the reaction of 2-pyrimidinediamine with the structural formula (IM) with an amine of the formula РВ7-И 2-МНЕ c, where 17, 7 and BC are defined above for the structural formula with (I), in order to form 2,4-pyrimidinediamine with the structural formula (I), or prodrugs according to the structural formula (II).

In yet another example, this method involves reacting 4-amino-2-pyrimidinamine according to

Go! of structural formula (M) (in which ВЕ" is an amino group) with an amine of the formula B7-II -МНЕ С, where |, В? and ВС are defined previously for structural formula (II), in order to form 2,4-pyrimidinediamine according to of structural formula where (I), or prodrugs according to structural formula (I). Alternatively, 4-amino-2-pyrimidinamine - can react with a compound of formula B-I 2-|0, where VK and I? defined earlier for the structural formula (I), and Y C represents a substitution group. o In yet another example, this method involves carrying out the halogenation reaction of 4-hydroxy-2-pyrimidinamine 4 according to the structural formula (M) (BK represents a hydroxyl group) with in order to form 2-pyrimidinamine according to the structural formula (IM), followed by the reaction of this pyrimidineamine with the corresponding amine as described above.

In yet another example, this method involves a halogenation reaction of M4-substituted cytosine

Pho according to the structural formula (MI) in order to form 4-pyrimidinamine according to the structural formula (HER) and reacting this pyrimidineamine with the corresponding amine as described above. o The 2,4-pyrimidinediamine compounds of the present invention are strong inhibitors of degranulation of immune cells, such

Ckz as mast cells, basophils, neutrophils and/or eosinophil cells. Thus, in yet another aspect, the present invention provides methods of regulating, and in particular inhibiting, the degranulation of such cells. The proposed method 60 generally comprises contacting the degranulating cell with a 2,4-pyrimidinediamine compound, or prodrugs according to the present invention, or with an acceptable salt, hydrate, solvate, M-oxide, and/or other composition thereof, in an amount, sufficient to effectively regulate or inhibit cell degranulation. This method can be used exogenously or exogenously as a therapeutic approach to the treatment or prevention of diseases characterized by, caused by, or associated with cellular degranulation. 65 Without intending to be bound by any theory of operation, biochemical evidence supports that 2,4-pyrimidinediamine compounds exert an inhibitory effect on degranulation, at least in part, by blocking and inhibiting the signal transduction cascade(s) initiated by cross-linking

E-receptors of high affinity for IDE ("Ps is KI") and/or Ids ("Psu KI"). Indeed, 2,4-pyrimidinediamine compounds are potent inhibitors of degranulation mediated by both EsKI and SKI receptors.

Consequently, the 2,4-pyrimidine compounds can be used to inhibit the signaling cascades of said Es receptors in any type of cell expressing such Es KI and/or Psu KI receptors, including but not limited to macrophages, mast cells, basophils, neutrophils and/or eosinophil cells.

These methods also make it possible to regulate, and in particular, to inhibit the processes that proceed in the direct direction and are the result of the activation of such signal cascades of E-receptors. Such processes include, 70 but are not limited to the following: Ese KI- and/or Ese KiI-mediated degranulation, cytokine production, and/or production and/or secretion of lipid mediators such as leukotrienes and prostaglandins. This method generally consists of bringing cells from the category above, expressing the E-receptor, in contact with a 2,4-pyrimidinediamine compound or prodrugs according to the present invention, or with an acceptable salt, hydrate, solvate, M-oxide and/or similar composition in an amount sufficient to effectively regulation or inhibition of the E-receptor signaling cascade, and/or a direct process dependent on the activation of this signaling cascade. This method can be applied ip miigo or ip mimo as a therapeutic approach to the treatment or prevention of diseases characterized by, caused by, or associated with with a signal cascade

E-receptors, such as diseases, are due to the release of specific chemical mediators of granules in the process of degranulation, the release and/or synthesis of cytokines, and/or the release and/or synthesis of lipid mediators, such as leukotrienes and prostaglandins.

In yet another aspect, the present invention provides methods for the treatment and/or prevention of diseases characterized by, caused by, or associated with the release of chemical mediators as a result of activation of signaling cascades of Pc receptors, such as the signaling cascades of Es KI and/or Esu KiI receptors . These methods can be used on animals for veterinary purposes or on humans. These methods generally include the administration of a quantity of a 2,4-pyrimidinediamine compound or prodrug of the present invention, or an acceptable salt, hydrate, solvate, M-oxide thereof, and/or a similar composition effective in treating or preventing a disease, to an animal or human. . As discussed earlier, the activation of the Ese KI signaling cascade or

Activation of KI receptors in certain immune cells leads to the release and/or synthesis of various chemicals that are pharmacological mediators of a wide variety of diseases. Any of these diseases can be treated or prevented by the methods of this invention. F

For example, in mast cells and basophils, the activation of Es signaling cascades is KI or Esu KI! leads to the immediate (from 1 to 3 minutes from the moment of receptor activation) release of preformed mediators "-- atopic reaction and/or type I hypersensitivity reaction / for example, histamine, proteases such as tryptase, si, etc.) with the help of degranulation processes. Such atopic reactions or hypersensitivity reactions type, include but are not limited to anaphylactic reactions to environmental and other allergens (eg, pollen, insect and/or animal venom, food, drugs, contrast dyes, etc.), anaphylactoid reactions, hay fever, allergic conjunctivitis, allergic rhinitis, allergic asthma, atopic dermatitis, eczema, urticaria, impaired functions of the mucous membrane, tissues and certain gastrointestinal disorders. 50 The immediate release of preformed mediators via degranulation is followed by the release and/or subsequent synthesis of a variety of other chemical mediators, including, among others, platelet-activating factor (RAF), prostaglandins, and leukotrienes (e.g., TC4) and de pomo synthesis and release. cytokines, for example TMEo,

I/-4, 1-5, 1-6, 11-13, etc. The first of these two processes occurs approximately 3 to 30 minutes after receptor activation; the second, approximately 30 minutes to 7 hours after receptor activation. It is believed that these "late-stage" mediators are partially responsible for the chronic symptoms of the above-mentioned atopic reactions and Type I hypersensitivity reactions and are also chemical mediators of inflammation and inflammatory diseases (for example, osteoarthritis, inflammatory bowel disease, ulcerative colitis,

Crohn's disease, idiopathic inflammatory bowel disease, irritable bowel syndrome, mucositis, etc.), - low degree of scarring (for example, scleroderma, increased fibrosis, keloid formation, postoperative scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury, and post myocardial infarction), and a complex or dryness syndrome. All these diseases can be treated or prevented by the methods of this invention.

Additional diseases that can be treated or prevented according to the methods of this invention include diseases associated with basophil and/or mast cell pathology. Examples of such diseases include, but are not limited to, skin diseases such as scleroderma, heart diseases such as

Ge) post-myocardial infarction, lung diseases, such as changes or transformation of lung muscles or chronic obstructive pulmonary disease (COPD), and intestinal diseases, such as inflammatory bowel syndrome (mucous colitis). The 2,4-pyrimidinediamine compounds of this invention are also potent tyrosine kinase inhibitors, namely 60 Zuk kinase. Thus, in yet another aspect, the present invention provides methods of regulating, and in particular, inhibiting the activity of Zuk kinase. The method generally consists in bringing bZuk-kinase, or a cell containing zZuk-kinase, into contact with a 2,4-pyrimidinediamine compound or prodrugs of this invention, or their acceptable salt, hydrate, solvate, M-oxide and/or similar composition in an amount effective to regulate or inhibit Zuk kinase activity. In one example, the Zuk kinase is an isolated or recombinant Zuk kinase. In another example, Zuk-kinase is an endogenous or recombinant 5ukK-kinase expressed by a cell, such as a mast or basophil. This method can be applied ip miigo or ip mimo as a therapeutic approach to the treatment or prevention of diseases characterized by, caused by, or associated with the activity of zuk-kinase.

Without intending to be bound by any particular theory of operation, the 2,4-pyrimidinediamine compounds of the present invention are believed to inhibit cell degranulation and/or the release of other chemical mediators primarily through inhibition of Zuk kinase, which is activated via the homodimer of the Es KI gamma chain (see Fig. 2). This gamma chain homodimer is partially taken up by other Es receptors, including Esu CI, Esu CI, and Pso CI.

For all these receptors, the process of intracellular signal transmission is mediated by a common homodimer of the 70 gamma chain. Binding and aggregation of these receptors leads to the recruitment and activation of tyrosine kinases, such as Zuk kinase. As a result of this joint signaling activity, the described 2,4-pyrimidinediamine compounds can be used to regulate, and in particular inhibit, signaling cascades

Es-receptors having this homodimer of the gamma chain, such as Esye KI, Esu KI, Esu KI and Eso, KI, as well as cell responses obtained through these receptors.

Zuk kinase is known to play a critical role in other signaling cascades. For example, Zuk kinase is an effector of B-cell receptor (B-cell receptor) signaling (Tigpeg et al., 2000, Imtypoiodu Todau 21: 148-154), and is also an essential component of the beta (1), beta (2) and beta signaling pathways (3) integrin in neutrophils | Moszai et al., 2002,

Iptipyu 16: 547-558). Since the described 2,4-pyrimidinediamine compounds are potent ZukK kinase inhibitors, they can be used to regulate and, in particular, inhibit any signaling cascades in which

BZuk-kinase plays a role, for example, in the signaling cascades of E-receptors, VSK, and integrin, as well as the cell responses obtained through these signaling cascades. Regulation or inhibition of a particular cellular response depends in part on the specific cell type and receptor signaling cascade, as is well known in the art. Non-limiting examples of cellular responses that can be regulated or inhibited by 2,4-pyrimidinediamine compounds include respiratory tract rupture, cell adhesion, cell degranulation, cell spreading, cell migration, phagocytosis (e.g., in macrophages), calcium ion flux (e.g., in mast cells, basophils, neutrophils, eosinophils, and B cells), platelet aggregation, and cell maturation (eg, in B cells).

Thus, in another aspect, the present invention provides methods of regulating and, in particular, inhibiting signaling cascades in which Zuk kinase participates. In general, this method consists of contacting a Zuk-dependent receptor or a cell expressing a Zuk-dependent receptor with a 2,4-pyrimidinediamine compound or prodrug of the present invention, or an acceptable salt, hydrate, solvate, M-oxide thereof, and /or their composition in b» amount, sufficient for effective regulation or inhibition of the signaling cascade. These methods can also be used to regulate and, in particular, inhibit direct processes or cellular responses resulting from the activation of individual ZukK-dependent signaling cascades. These methods can be used to regulate any signaling cascades in which the role of Zuk kinase is unknown or established later. These methods can also be used ip migo or ip mimo as a therapeutic approach to treat or prevent diseases characterized by, caused by, or associated with the activation of the Zuk-dependent signaling cascade.

Non-limiting examples of such diseases include the diseases previously described.

Data from studies at the cellular level and data from studies in animals also indicate that the 2,4-pyrimidinediamine compounds of this invention can be used for the treatment or prevention of autoimmune diseases and/or symptoms of such diseases. The methods generally consist in the application by a person suffering from an autoimmune disease or at increased risk of developing a disease, a dose of "» 2,4-pyrimidinediamine agent or prodrugs of this invention, or their acceptable salt, M-oxide, hydrate, solvate, or their combination, in an amount sufficient to effectively treat or prevent autoimmune diseases and/or associated symptoms.Autoimmune diseases that can be treated or prevented with (se) 2,4-pyrimidinediamine compounds include diseases commonly associated with non-anaphylactic hypersensitivity reactions (type I, type III, and/or type IM hypersensitivity reactions) and/or diseases that are mediated, at least in part, by activation of the Esu K signaling cascade in monocytes. Such autoimmune diseases include, but are not limited to, autoimmune diseases that are often attributed to autoimmune disorders of one organ or one type of cells or those that are often attributed to systemic auto minor violations. Non-limiting examples of diseases that are often attributed to autoimmune disorders

GI of one organ or one cell type, including autoimmune thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, syndrome

Goodpasture, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Bazed disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis, and membranous glomerulopathy.

Non-limiting examples of diseases that are often referred to as systemic autoimmune disorders include

F, systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome,

Because of polymyositis-dermatomyositis, systemic sclerosis, nodular periarteritis, multiple sclerosis, bullous pemphigoid.

Figure 1 illustrates allergen-induced IDE production and subsequent release of preformed and other 60 chemical mediators from mast cells;

Fig. 2 illustrates the signal transduction cascade of Ese KI receptors, which leads to degranulation of mast cells and/or basophils;

Fig. 3 illustrates the possible points of activity of compounds that selectively inhibit degranulation in the reverse direction, mediated by Es is Ki-receptors, and compounds that inhibit degranulation mediated by Es is bo VI-receptors and induced by ionomycins;

Fig. 4 provides a graphic illustration of the effect of certain 2,4-pyrimidinediamine compounds, OM5O (control) and ionomycins on the Ca flux in cultured human mast cells (SCMS);

Fig. 5 shows a graphic illustration of the rate of inhibitory activity of compounds KU21218 and K926495;

Fig. 6 illustrates the effect of washout on the inhibitory activity of compounds KU21218 and K921302;

Figure 7 shows data showing how varying concentrations of the compounds KU21218 (A) and KU21219 (B) inhibit the phosphorylation of various proteins downstream of Zuk kinase in the signal transduction cascade.

IDE receptors in activated bone marrow mast cells (BMMS);

Fig. 8 illustrates data showing the inhibition of endogenous substrate (I AT) and peptide substrate phosphorylation depending on the dose of Zuk-kinase phosphorylation with increasing concentration of compounds K921218 (X), 70. K921219 (Y) and K921304 (7);

Fig. 9 illustrates data showing that the inhibition of Zuk-kinase by the compound KU21219 is competitive with respect to ATP;

Fig. 10 illustrates data showing that the compounds K9U21219 (A) and K218218 (B) at different concentrations inhibit the phosphorylation of proteins following Zuk kinase, but not IMM kinase, in the signal transduction cascade of Essay Ki-receptors in activated CHMS cells; also shows inhibition of phosphorylation of proteins following UM kinase, but not Zuk-kinase, in the presence of a known inhibitor (PP2) of UM kinase;

Fig. 11A-110 provide data that demonstrate the inhibition of protein phosphorylation in the direct direction from zZuk-kinase in the signal transduction cascade of Ese KI-receptors in VMMC cells;

Fig. 12 provides a graphic illustration of the effectiveness of the compound KU21302 in modulating arthritis induced by antibodies to collagen (SAIA) in mice;

Fig. 13 provides a graphic illustration of the effectiveness of the K9O21302 compound in the SAIA model, in comparison with other means and control substances;

Fig. 14 provides a graphic illustration of the effectiveness of the compound KUO21302 in modeling collagen-induced arthritis (SIA) in rats; at

Fig. 15 provides a graphical illustration of the effectiveness of the compound K9O21302 in inhibiting experimental autoimmune encephalomyelitis (EAE) in mice, which is a clinical model of multiple sclerosis, and

Fig. 16 provides a graphic illustration of the effectiveness of the K921302 compound in a study on mice 5), which on the first day of immunization were administered a dose of 15 µg RI R. 139-151/200 µg MTB (CEA). (se)

Definition

The following terms used in this text have the following meanings: F "Alkyl" alone or as part of another substituent refers to a saturated or unsaturated che monovalent hydrocarbon radical with a branched, unbranched or cyclic structure having a fixed number of carbon atoms (ie, C1-C6 means one to six carbon atoms), and is obtained by removing one hydrogen atom from one carbon atom of the original alkane, alkene or alkyne. Typical alkyl oo groups include, but are not limited to: methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1- yl, cycloprop-1-en-1-yl, cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1- yl, but-1-en-2-yl, « 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1 ,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien -1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-Z-yn-1-yl, a, etc.; and the like. Where specific levels of saturation are intended, the terms "alkanyl," "alkenyl," and/or "alkynyl" are used, as defined below. In preferred embodiments of the invention, the alkyl groups are (C1-C6) alkyl. "Alkanyl" by itself or as part of another substituent refers to a saturated or unsaturated alkyl with (ee) branched, unbranched, or cyclic structure obtained by the removal of one hydrogen atom from a single carbon atom of the parent alkane. Typical alkanyl groups include, but are not limited to, the following: methanyl; ethanyl; propanyls such as: propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, - etc. butanyls such as: butan-1-yl, butan-2-yl (les-butyl) , 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (1-butyl), cyclobutan-1-yl, etc.; and the like. In preferred embodiments of the invention, and alkanyl groups represent (C1-C6) alkanyl. in "Alkenyl" independently or as part of another substituent refers to saturated or unsaturated alkyl with a branched, unbranched a branched or cyclic structure having at least one carbon-carbon double bond and obtained by removing one hydrogen atom from one carbon atom of the original alkene. This group can have a cis or trans configuration around the double bond. Typical alkenyl groups include, but are not limited to: ethenyl; propenyls, such as: prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl, iF) prop-2-en-2-yl, cyclohor-1 -en-1-yl; cycloprop-2-en-1-yl; butenyls, such as: but-1-en-1-yl, but-1-en-2-yl,

Ho) 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta- 1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like In preferred embodiments of the invention, the alkenyl group is (C2-Cb) alkenyl. "Alkynyl" alone, or as part of another substituent, refers to a saturated or unsaturated alkyl having a branched, unbranched or cyclic structure having at least one carbon-carbon triple bond and obtained by removing one hydrogen atom from one carbon atom of the parent alkyne.

Typical alkynyl groups include, but are not limited to: ethynyl; propynyls such as prop-1-yn-1-yl, 65 prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like. In preferred embodiments of the invention, the alkynyl group is (C2-Cb) alkynyl.

"Alkyldiyl" by itself or as part of another substituent refers to a saturated or unsaturated divalent hydrocarbon group with a branched, unbranched or cyclic structure having a fixed number of carbon atoms (for example, C1-Cb means from one to six carbon atoms) and is obtained by the elimination of one of a hydrogen atom from each of two different carbon atoms of the parent alkane, alkene, or alkyne, or by removing two hydrogen atoms from a single carbon atom of the parent alkane, alkene, or alkyne.

Two monovalent radical centers or each valency of a divalent radical center can form a bond with the same or different atoms. Typical alkyldiyl groups include, but are not limited to, the following: methanediyl; ethyldiyls such as ethane-1,1-diyl, ethane-1,2-diyl, ethene-1,1-diyl, ethene-1,2-diyl; 70 propyldiyls such as propane-1, 1-diyl, propane-1,2-diyl, propane-2,2-diyl, propane-1, C-diyl, cyclopropane-1, 1-diyl, cyclopropane-1,2 -diyl, prop-1-ene-1,1-diyl, prop-1-ene-1,2-diyl, | prop-2-ene-1,2-diyl, prop-1-ene-1,3-diyl, cycloprop-1-ene-1,2-diyl, cycloprop-2-ene-1,2-diyl, icycloprop- 2-ene-1, 1-diyl, prop-1-yne-1,3-diyl, etc.; butyldiyls such as butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, butane-1,4-diyl, butane-2,2-diyl, 2-methyl-propane- 1,1-diyl, 2-methyl-propane-1,2-dil, cyclobutane-1,1-diyl; cyclobutane-1,2-diyl, cyclobutane-1, Z-diyl, but-1-ene-1,1-diyl, but-1-ene-1,2-diyl, but-1-ene-1,3- diyl, but-1-ene-1,4-diyl, 2-methyl-prop-1-ene-1,1-diyl, 2-methanilidene-propane-1, 1-diyl, buta-1,3-diene- 1, 1-diyl, buta-1,3-diene-1,2-diyl, buta-1,3-diene-1, Z-diyl, buta-1,3-dien-1,4-diyl, cyclobut- 1-ene-1,2-diyl, cyclobut-1-ene-1,3-diyl, cyclobut-2-ene-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl, cyclobuta- 1,3-diene-1,3-diyl, but-1-yne-1,3-diyl, but-1-yne-1,4-diyl, buta-1,3-diyne-1,4-diyl, etc., and the like. If certain saturation levels are meant,

The terms "alkanyldiyl", "alkenyldiyl" and/or "alkanyldiyl" are used. If it is assumed that two valences of the same carbon atom are involved, the name "alkylidene" is used. In preferred embodiments of the invention, the alkyldiyl group is (C1-Cb) alkyldiyl. Also, preference is given to saturated non-cyclic alkanyldiyl groups, in which the radical centers are located near the terminal carbon atoms, for example, methanediyl (methano); ethane-1,2-diyl (ethano); propane-1,3-diyl (propane); butane-1,4-diyl (butane); and c the like (also known as alkylenes, which are defined below). "Alkylene-- independently or as part of another substituent refers to an unbranched saturated or (o) unsaturated alkyldiyl group having two terminal monovalent radical centers obtained by removing one hydrogen atom from each of the two terminal carbon atoms of an unbranched initial alkane, alkene or alkyne. Designation double or triple bonds, if any, in certain alkylene groups are indicated in square brackets. Typical alkylene groups include, but are not limited to, methane-; ethylene-, such as ethane-, ethene-, ethyne -; propylene-, such as propane-, propy)ene-, propa| 1,2|diene-, propyyne-, etc.; butylene-, b» such as butane-, butICene-, butIL|ene-, buta(| (1,Z|diene-, but|Lin-, butiIL|Iin-, buta|1,3|diene-, etc.; and "- the like. If specific levels of saturation are meant, then the terms "alkane-" are used, "alkene-" and/or "alkyne--. In preferred embodiments of the invention, the alkylene group is (C1-C6) or (C1-C3) with c5 alkylene-. It is also preferred not branched saturated groups of alkane-, for example, methane-, ethane-, so propane-, butane-, and the like. "Heteroalkyl," "Heteroalkanyl," "Heteroalkenyl," "Heteroalkynyl," "Heteroalkyldyl," and "Heteroalkylene," by themselves or as part of another substituent, refer to alkyl, alkynyl, alkenyl, alkynyl, alkyldiyl, and alkylene groups, respectively, in which one or more carbon atoms are independently substituted by the same or different heteroatoms or heteroatom groups. Typical heteroatoms and/or heteroatomic groups that can replace carbon atoms include, but are not limited to, the following: О-, -5-, -5-0-, -МК-, -РН-, -5(0)- , -5(0)25-, -(0)MK-, -50)2MK-, and the like, including their combinations, where each K' is independently hydrogen or with (C1-Cb) alkyl. "Cycloalkyl" and "Heterocycloalkyl" by themselves or as part of another substituent refer to the cyclic version of the "alkyl" and "heteroalkyl" groups, respectively. For heteroalkyl groups, the heteroatom may occupy the same position in which it is attached to the rest of the molecule. Typical Cycloalkyl Groups include, but are not limited to, cyclopropyls; cyclobutyls, such as cyclobutanyl and cyclobutenyl; cyclopentyls, such as co-cyclopentanyl and cyclopentenyl; cyclohexyls, such as cyclohexanyl and cyclohexenyl; and the like. Typical heterocycloalkyl groups include, but are not limited to, the following: tetrahydrofuranyl ( e.g., 5-tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, etc.), piperidinyls (e.g., piperidin-1-yl, piperidin-2-yl, (Ce), etc.), morpholinyls (e.g., morpholin-3-yl , morpholin-4-yl, etc.), piperazinyls (for example, piperazin-1-yl,

Pho piperazin-2-yl, etc.), and the like. "Noncyclic heteroatomic bridge" refers to a divalent bridge whose initial atoms are exclusively heteroatoms and/or heteroatomic groups. Typical noncyclic heteroatomic bridges include, but are not limited to, the following: О-, -5-, -5-0-, -МК-, -РН-, -5(0)-, -5(0)25-, - (OM -, -5(0)2MK-, and the like, including their combinations, where each K' radical independently represents a hydrogen atom or a (C1-C6) alkyl group.

GF) "Parent aromatic ring system" refers to an unsaturated cyclic or polycyclic system

Ф is a ring with a conjugated system of P-electrons. The definition of "parent aromatic ring system" specifically includes fused ring systems having one or more aromatic rings and one or more saturated or unsaturated rings, such as, for example, fluorene, indane, indene, phenalene, tetrahydronaphthalene, etc. Typical starting aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, indacene, z-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, 65 rubicene, tetrahydronaphthalene, triphenylene, trinaphthalene, and the like, and various hydroisomers of the specified compounds.

"Aryl" alone or as part of another substituent refers to a monovalent group of aromatic hydrocarbons with a fixed number of carbon atoms (so, C5-C15 means from 5 to 15 carbon atoms) and obtained by separating one hydrogen atom from a single carbon atom of the original system of aromatic rings. Typical aryl groups include, but are not limited to, groups derived from the following: aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, crownene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, avs-indacene, z-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like, and also various 7/0 subisomers of the specified compounds. In preferred embodiments of the invention, the aryl group is (C5-C15) aryl, or preferably with the structure (C5-C10). The most preferred aryls are cyclopentadienyl, phenyl and naphthyl. "Arylaryl" by itself or as part of another substituent refers to a monovalent group of hydrocarbons obtained by removing one hydrogen atom from a single carbon atom of a ring system in which two or more identical or non-identical parent aromatic ring systems are connected directly to each other by a single a connection in which the number of such direct ring connections is one less than the number of involved starting systems of aromatic rings. Typical arylaryl groups include, but are not limited to, biphenyl, triphenyl, phenyl-naphthyl, binaphthyl, biphenyl-naphthyl, and the like. If the number of carbon atoms in the arylaryl group is specified, then this number is equal to the number of carbon atoms contained in each parent aromatic ring. For example, (C5-C15) arylaryl represents an arylaryl group in which each aromatic

The ring contains from 5 to 15 carbon atoms, for example, biphenyl, triphenyl, binaphthyl, phenylnaphthyl, etc. It is desirable that each starting aromatic ring system of the arylaryl group is an independent aromatic system (C5-C15), and preferably, a system (C5-C10). Also preferred are aryl groups having identical parent aromatic ring systems, eg, biphenyl, triphenyl, binaphthyl, trinaphthyl, etc. "Biaryl" by itself or as part of another substituent refers to the arylaryl group having two identical parent aromatic systems directly connected by a single bond. Typical biaryl groups include, but are not limited to, biphenyl, binaphthyl, bianthryl, and the like. It is desirable that the aromatic ring systems (8) are aromatic rings (C5-C15), and preferably (C5-C10) rings. It is especially desirable that the biaryl group is biphenyl. "Arylalkyl" by itself or as part of another substituent refers to a non-cyclic alkyl group in which one of the hydrogen atoms is bonded to a carbon atom, typically a terminal or 3-carbon atom, substituted with an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, io 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, pd naphthobenzyl ,2-naphthophenylethan-1-yl and the like. In the case of certain alkyl compounds, the terms "arylalkanyl", "arylalkenyl" and/or "arylalkynyl" are used. In preferred embodiments of the invention, the arylalkyl group is (C6-C21) arylalkyl, for example, the alkanyl, alkenyl or alkynyl fragment of the arylalkyl group has a (C1-Cb) structure, and the aryl fragment has a (C5-C15) structure. In preferred embodiments of the invention, an arylalkyl group with a (C6-C13) structure is preferred, for example, an alkynyl, alkenyl or alkynyl fragment of an arylalkyl group has a (C1-C3) structure, and an aryl fragment has a (C5-C10) structure. "Heteroaromatic initial ring system" refers to an aromatic ring initial system in which at least one or more carbon atoms are independently replaced by the same or different heteroatoms and/or heteroatomic groups. These typical heteroatoms or heteroatom groups include, but are not limited to, the following: p-M, MN, P, 0, 5, Z (0), Z (0)", 5i, etc. The definition of "initial heteroaromatic ring system" specifically includes fused ring systems with one or more aromatic rings and one or more saturated or unsaturated rings, such as benzodioxane, benzofuran, chroman, chromin,

Go! indole, indoline, xanthine, etc. The definition of "initial system of heteroaromatic rings" also includes known rings containing general substitution groups, such as benzopyrone and 1-methyl-1,2,3,4-tetrazole. The definition of "heteroaromatic initial ring system" does not include benzene rings fused to cyclic - polyalkylene glycols, such as cyclic polyethylene glycols A typical heteroaromatic initial ring system includes, but is not limited to, the following: acridine, benzimidazole, benzisoxazole, c benzodioxane, benzodioxole, benzofuran ) isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyradazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolysine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.

F) "Heteroaryl" alone or as part of another substituent refers to a monovalent heteroaromatic km group with a specified number of ring atoms (for example, "5-14--lenny" means the number of ring atoms from 5 to 14), obtained by removing one hydrogen atom from a specified atom of the initial system of heteroaromatic rings. Typical heteroaryl groups include, but are not limited to, groups derived from the following: acridine, benzimidazole, benzisoxazole, benzodioxane, benzodiazole, benzofuran, benzopyrone, benzothiadiazole, benzothiazole, benzotriazole, benzoxazine, benzoxazole, benzoxazoline, carbazole, p -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoiindole, isoiindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, 65 oxadiazole, oxazole, pyrimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran , pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,

quinolysine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthine, and the like, as well as various hydroisomers of these compounds. In preferred embodiments of the invention, preference is given to the group of 5-14-membered heteroaryl, and especially, 5-10-membered heteroaryl. "Heteroaryl-heteroaryl" by itself or as part of another substituent refers to a monovalent heteroaromatic group obtained by the separation of one hydrogen atom from a specified atom of a ring system in which two or more identical or non-identical initial heteroaromatic ring systems are directly connected to each other by a single bond language, in which the number of such ring connections is one less than the number of involved initial systems of heteroaromatic rings. Typical heteroaryl-heteroaryl groups include, but are not limited to, bipyridyl, tripyridyl, pyridylpurinyl, bipurinyl, and the like. With a given number of atoms, these numbers refer to the number of atoms that make up each of the initial systems of heteroaromatic rings. For example, 5-15-membered heteroaryl-heteroaryl represents a heteroaryl-heteroaryl group in which each initial system of heteroaromatic rings contains from 5 to 15 atoms, for example, bipyridyl, tripyridyl, etc. It is desirable that each initial system of heteroaromatic rings is independently a 5-15-membered 7/5 Heteroaromatic system, and preferably a -5-10--membered heteroaromatic system. Heteroaryl-heteroaryl groups in which all initial heteroaromatic ring systems are identical are also preferred. "Biheteroaryl" by itself or as part of another substituent refers to a heteroaryl-heteroaryl group having two identical initial systems of heteroaromatic rings connected directly to each other by a single bond. Exemplary biheteroaryl groups include, but are not limited to, bipyridyl, bipyrynyl, biquinolinyl, and the like. Systems with 5-15-membered heteroaromatic rings are preferred, and preferably with 5-10-membered heteroaromatic rings. "Heteroarylalkyl" by itself or as part of another substituent refers to a non-cyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or C-carbon atom, is replaced by a heteroaryl group. In the case of specific alkyl compounds, names such as c heteroarylalkanyl, heteroarylalkenyl and/or heteroarylalkanyl are used. In preferred embodiments of the invention, the heteroarylalkyl group is a 6-21-membered heteroarylalkyl, for example, an alkanyl, alkenyl, or o-alkynyl fragment of a heteroarylalkyl is an alkyl with the structure (C1-Cb), and the heteroaryl fragment is a 5-15-membered heteroaryl . A personal preference is given to 6-13-membered heteroarylalkyls, for example, an alkynyl, alkenyl or alkynyl fragment of a heteroarylalkyl is an alkyl with a (C1-C3) structure, and a heteroaryl fragment is a 5-10-membered heteroaryl. "Halogen" or "Haloid" alone or as part of another substituent generally refers to fluorine, chlorine, Me, bromine, and iodine groups. "- "Haloidoalkyl" by itself or as part of another substituent refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen. Thus, the term "haloalkyl" includes monohaloalkyls, dihaloalkyls, trihaloalkyls, etc., including perhaloalkyls. For example, the term "(C1-C2) haloalkyl" also includes fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, and the like.

The above groups may include prefixes and/or suffixes commonly used to form additional, well-known substitution groups. For example, "alkyloxy" or "alkoxy" refers to the group of "formula -OK", "alkylamine" refers to the group of formula -MNK" and "sylalkylamine" refers to the group of formula -c -MA"K", where each K" independently represents alkyl. In another example, "haloalkyloxy" or "haloalkyloxy" refers to a group of the formula -OK" where K" is haloalkyl. """Protecting group" refers to a group of atoms that mask, reduce, or block the reactivity of a functional group if they are attached to a reactive functional group in the molecule. Typically, the protecting group can be selectively removed during synthesis. Examples of protecting groups can be found in (Green and

Go! Watsa "Protecting groups in organic chemistry", 3rd edition, 1999, ed. J. Wiley and Sane, New York (Ogeepe apa MUtsiv, Rgoiesime OSgocrz ip Ogdapis Spitivighu, Z Ei. 1999, dopp MMyPeu 5 Bopv, MU), as well as in the book by Harrison et al. a brief overview of the methods of synthetic organics", vol. 1-8, 1971-1996, John Wiley and Sane, - New York (Nagtizop ei ai, Sotrepaisht oi Zupipeis Ogdapis Meijosv, Moiv. 1-8, 1971-1996, dopp MUyeu 5 Bopv,

MM)). Representative amino protecting groups include, but are not limited to, formyl, acetyl, o trifluoroacetyl, benzyl, benzyloxycarbonyl ("CB2"), tert-butoxycarbonyl ("BOC"), trimethylsilyl ("TM"),

Pr 2-trimethylsilyl-ethanesulfonyl CTE, trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("EMOS"), nitro-veratryloxycarbonyl ("MMOS") and the like. Representative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is acylated or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (eg, TMS or TIRR5B groups), and allyl ethers. (F, "Prodrugs" refers to the derivative of the active compound of 2,4-pyrimidinediamine (drugs), which requires

Go) transformation under the conditions of use, for example inside the body, in order to release active 2,4-pyrimidinediamine. Prodrugs are often, but not necessarily, pharmacologically inactive until they are converted to 60% active drugs. Prodrugs are typically obtained by masking a functional group that is part of a 2,4-pyrimidinediamine-containing drug in order to activate the progroup (defined below) to further form the procomponent, which then undergoes transformation, such as cleavage under specific conditions of use with with the aim of isolating the functional group, and therefore the drugs containing the active form of 2,4-pyrimidinediamine. Cleavage of the procomponents can occur spontaneously, for example by a hydrolysis reaction, or under the influence of a catalyst or other agent, such as an enzyme, light, acid or alkali, and also as a result of a change or influence of any physical parameter or environment, such as a change in temperature. The agent may be endogenous (internal) in terms of the conditions of application, such as an enzyme present in the cells for which these drugs are intended, or the acidic conditions of the stomach, or it may be administered exogenously.

A wide variety of progroups and procomponents suitable for masking functional groups in active 2,4-pyrimidinediamine compounds in order to obtain prodrugs is well known in practice. For example, a hydroxyl functional group can be masked as a sulfonate, an ether, or as a carbonate moiety that can be hydrolyzed in situ to form a hydroxyl group. The amino functional group can be masked as an amide, carbamate, imine, urea, phosphenyl, phosphoryl, or sulfenyl procomponent, which can be hydrolyzed in situ to yield an amino group. The carboxyl group can be masked as an ester (including silyl ethers and thioethers), an amide or hydrazide procomponent, which can be hydrolyzed immeasurably to give the carboxyl group. Other specific examples of suitable progroups and their respective procomponents will be apparent to those skilled in the art. "Progroup" refers to a type of protective group that, when used to mask the functional /5 Group in drugs containing active 2,4-pyrimidinediamine, to form a procomponent, turns the drug into a prodrug. Progroups are typically connected to functional groups of drugs through bonds that can break down under the specified conditions of use. Thus, the progroup is that part of the procomponent that disintegrates to release the functional group under the specified conditions of use. As a specific example, we can cite the procomponent of amide, which has the formula -МН-С(О)СН» and contains the progroup -(О)СН». "E-Receptor" refers to a member of a family of cell surface molecules that binds the E-portion of an immunoglobulin (which contains a specific constant region). Each E-receptor binds immunoglobulins of a certain type. For example, Eso, -receptor ("Pso, K") binds IdA, Eso K binds IDE and Eso K binds Id.

The Eso K-family includes the polymeric Id receptor involved in epithelial transfer IDALOM, mycloid specific receptor Kso, KI (which is also called CO89), Es o; /in K, and at least two alternative IA c receptors, see Mopieigo 5 map de M/ipKei, 2003, Appy. Kew. Ittipoi, admapseid e-ribriisayop). Eso, KI is expressed on neutrophils, eosinophils, monocytes/macrophages, dendritic cells and Kupffer cells. Eso KI consists of one alpha chain and GSK gamma homodimer, which carries an activation motif (ITAM) in the cytoplasmic region and phosphorylates 5ukK-kinase.

The Ese KE family includes two types of receptors called Ese VI and Ese VI! (also known as CO23). Essay BI (0) is a high-affinity receptor (binding CHE with an affinity of about 10 "9M7) found on mast cells, basophils and eosinophil cells that retain monomeric IDE on the cell surface. Essay

CI has one alpha chain, one beta chain, and the homodimeric gamma chain described above. Essay KI! is a low-affinity receptor expressed on mononuclear phagocytes, B-lymphocytes, eosinophils, and platelets. Essay KI! contains a single polypeptide chain, and does not include a gamma chain homodimer.

The Esu K family includes three types called Esu KI (also known as COb4), Esu KII (also known as so

СО32), and Esu KI (also known as СО 16). Esu KI is a receptor with high affinity (binds Idsi with an affinity of about 10 MM), which is located on mast cells, basophils, mononuclear cells, neutrophils, eosinophils, dendritic and phagocytic cells, and retains monomeric IdsS on the surface " 470 Cells. Esu CI includes one alpha chain and a gamma chain dimer, which is included in Eso, CI and Ese CI. -o c Esu KII is a low-affinity receptor expressed on neutrophils, monocytes, eosinophils, platelets, and B-lymphocytes. Esu KII includes a single alpha chain and does not include the gamma chain homodimer, described above.

Esu KIII is a receptor with low affinity (still binds with affinity 5xO 5M7), expressed on MK, eosinophils, macrophages, neutrophils and mast cells. It contains one alpha chain and a gamma homodimer, (og) which is included in Eso, KI, Ese KI and Esu KI. Those skilled in the art will agree that the proposed subunit structure and binding characteristics of these various ERs receptors, as well as the types of cells that express them, have not been fully characterized. The above only reflects the general picture of the current state of these receptors, see for example, Ittypobioiodu: "se 20 Te Ittype Zuziet ip Neay 8 Oiveaze, B Edayiop, Uapezhau ei ai., Ed", 2001, I5VM 0-8153-3642-x, Ridyge 9.30 ai yr.371), and is not aimed at limiting set of receptor signaling cascades that can be regulated by the compounds described in this application. "Es-Receptor-mediated degranulation" or "Es-Receptor-induced degranulation" refers to degranulation that occurs through the signal transduction cascade of the PEs receptor, initiated by cross-linking of the Es receptor.

GF! "DE-mediated degranulation" or "Es CI-mediated degranulation" refers to degranulation that occurs through the signal transduction cascade of the IDE receptor, initiated by the cross-linking of ESEs bound by Es CIs. Cross-linking can be caused by an allergen-specific ISE or another multivalent binding agent, such as an anti-I9E antibody. In Fig. 2, in mast and/or basophilic cells, the KiI signaling cascade leading to degranulation can be divided into two stages: reverse and forward.

The reverse stage includes all processes that occur before the mobilization of the calcium ion (illustrated as "Ca 77" in Fig.2; see also Fig.3). The direct stage includes the mobilization of calcium ions and all its subsequent direct processes.

Compounds that inhibit Ese KiI-mediated degranulation can act at any step in the direction of Ese 65 RI-mediated signal transduction cascade. Compounds that selectively inhibit degranulation mediated by Ese KI in the reverse direction act so as to inhibit that part of the signaling cascade of Ese KI in the opposite direction from the point at which the mobilization of calcium ions is caused. In cellular assays, compounds that selectively inhibit EsCI-mediated degranulation in the reverse direction also inhibit the degranulation of cells such as mast cells or basophils that are activated or stimulated by an allergen-specific IDE or binding agent (such as anti-I (DE antibody), but do not markedly inhibit degranulation of cells that are activated or stimulated by degranulation agents that bypass the Es signaling pathway, such as the calcium ionophore ionomycin and A23187. "Idb-induced degranulation" or "Degranulation. mediated by Es in KI" refers to degranulation, which occurs with the help of a signal transduction cascade of Es in Ki-receptors, initiated by 70 cross-linking of Ids bound by Es in KI. Cross-linking can be initiated by allergen-specific ISE or other multivalent binder agent, such as anti-Ido or an antibody fragment.Like the Es signaling cascade of Ki receptors, the Es Ki signaling cascade I-receptors in mast and basophilic cells leads to degranulation, which can be divided into the same two stages: reverse and forward.

Similar to Rce Ki-mediated degranulation, compounds that selectively inhibit degranulation, 72 mediated by Esu KI in the reverse direction, act in the opposite direction from the point at which the mobilization of calcium ions is induced. In cellular studies, compounds that selectively inhibit Esu CI-mediated degranulation in the reverse direction also inhibit degranulation of cells, such as mast cells or basophils, that are activated or stimulated by an allergen-specific IDE or binding agent (such as anti-O antibody or its fragment), but do not significantly inhibit the degranulation of cells that are activated or stimulated by degranulating agents bypassing the Es signaling pathway in KI, for example, calcium ionophore -ionomycin and A23187. "Ionophore-induced degranulation" or "Ionophore-mediated degranulation" refers to the degranulation of a cell, such as a mast or basophil, that occurs as a result of exposure to a calcium ionophore, such as, for example, ionomycin or A23187. | And | AND

Zuk-Kinase" refers to the well-known spleen protein tyrosine kinase non-receptor 72kOa Go) (cytoplasmic), expressed in B-cells and other hematopoietic cells. Zuk-kinase includes two consecutive consensus ogs-homology 2 (ZH2) domains, which binds to the phosphorylated motifs of immunoreceptors based on tyrosine (MIBT), linker domains and catalytic domains | for a review of the structure of "co 20 and the function of ZukK-kinase, see Zada et al., 2001, 9. Viospet. (ToKuso) 130:177 -186 (see also Tygpeg et al., 2000, IttypoYodu Todau 21:148 -154). Zuk-kinase has been intensively studied as a factor influencing the signaling (o) receptor of B cells (BSC) | Gygpeg et al, 2000, virga )|. Zuk-kinase is also a critical factor for tyrosine phosphorylation of many proteins that regulate an important pathway leading from immunoreceptors, such as cascades -- mobilization of Ca?- and mitogen-activated protein kinase (MAPK) cascades (see Fig. 2 ) and degranulation. Zuk-kinase c zv also plays a critical role in integrin signaling in neutrophils | see, for example, Moszai et al. 2002, co

Ittipyu 16:547 -5581I.

As used herein, Zuk kinase includes kinase from any species of animal, including but not limited to humans, monkeys, cattle, pigs, rodents, etc. belonging to the Zuk family. This group specifically includes isoforms, splicing variants, allelic varieties, mutants of natural and artificial origin. "

The amino acid sequences of such bZuk kinases are well known and available through SEMVAMK (bank of genetic material). Specific examples of tkMAvz-encoding of different isoforms of human Zuk-kinase can be found in

SEMVAMK under the following numbers: ді|21361552|гейМмМ 003177.2|, 9а|496899|етр|229630.1|ИНБ5УКРТК И|496899) :з» and 9і|15030258|95|IVSO11399.128С011399 (15030258), which are included in this statement as a reference .

Those skilled in the art will appreciate that tyrosine kinases belonging to other families may have active sites or binding pockets with a three-dimensional structure similar to the ZukK structure. As a result of this structural similarity, it is believed that such kinases, hereinafter - "ZUuK imitators", can serve as catalysts for the phosphorylation of substrates that are phosphorylated by Zuk kinase. Thus, it becomes clear that such ZukK mimics, the signal transduction cascades in which such Zuk mimics play a role, and the biological reactions that take place - thanks to these ZukK mimics and signaling cascades dependent on such ZukK mimics can be regulated , and

In particular, inhibit with the 2,4-pyrimidinediamine compounds described in this application. (se) "Buk-Dependent Signaling Cascade" refers to a signal transduction cascade in which buk kinase plays a role. Non-limiting examples of such Zook-dependent signaling cascades include Eso, CI, Ese CI I, Esu CI,

Esu KI, VSK and integrin signaling cascades.

"Autoimmune diseases" include diseases that are usually associated with non-anaphylactic hypersensitivity reactions (type II, type Ш, and/or type IM hypersensitivity reactions), which are caused by a cell-mediated and/or humoral immune response of the body to one or more immunogenic (F) substances of endogenous and/or exogenous origin. These autoimmune diseases are different from diseases associated with anaphylactic hypersensitivity reactions (type I or mediated by CE).

Compounds of 2,4-pyrimidinediamines 60 The compounds of this invention are mainly 2,4-pyrimidinediamine compounds with the structural formula (1): b5 b

Кк ве 2 Ло и ве Ye mya?

H H including their salts, hydrates, solvates and M-oxides, where:

I" and 12 are each independently selected from the group consisting of a direct link and a linker;

B2 is selected from the group containing (C1-C6) alkyl, arbitrarily substituted by one or more identical or different KZ groups, (C3-C8) cycloalkyl, arbitrarily substituted by one or more identical or different groups 8, cyclohexyl, arbitrarily substituted by one or more by the same or different groups in, 3-8--ene cycloheteralkyl, arbitrarily substituted by one or several identical or different groups 8, (C5-C15) aryl, arbitrarily substituted by one or several identical or different groups KZ, phenyl, arbitrarily substituted by one or several by the same or different groups of KZ and 5-15-membered heteroaryl, arbitrarily substituted by one or several same or different groups in; Ha! 7 is selected from the group containing hydrogen, (C1-Cb) alkyl, arbitrarily substituted by one or more of the same or different groups 8, (C3-C8) cycloalkyl, arbitrarily substituted by one or more of the same or different groups 8, cyclohexyl, arbitrarily substituted by one or several identical or different groups 8, 3-8-membered cycloheteroalkyl, arbitrarily substituted by one or several identical or different groups 8, (C5-C15) aryl, arbitrarily substituted by one or several identical or different KZ groups, phenyl , arbitrarily substituted by one or more identical or different groups BZ and 5-15-membered F» heteroaryl, arbitrarily substituted by one or several identical or different groups in; "-- vo is selected from the group containing vo, (C1-C6) alkyl, arbitrarily substituted by one or several identical or different groups K, (C1-C4) alkanyl, arbitrarily substituted by one or several identical or different ch groups KZ, ( C2-C4) alkenyl, arbitrarily substituted by one or several identical or different groups K and c (C2-C4) alkynyl, arbitrarily substituted by one or several identical or different groups 8;

Each 29 is independently selected from the group consisting of hydrogen, an electronegative group, -OK 4 588, (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, -MEOB-, halogen, (C1-C3) haloalkyl, (C1- c3) « 20 perhaloidoalkyl, -SEz, -СНоСЕ»z, -"СЕоСЕз, -СМ, -МС, -ОСМ, -ВСМ, -МО, -МО», -Мз, -В(ОВ8, -8(0) 589. . 0)О89, -осС(ОМесвВе, -ЗВС(ОМееВе, ,» -ос(Мн)Ме свг, -вс(Мн)уМе в, -ИМНе(ОоДВУ, Мне, -ИМНе(OodMegsve and -IMNO(MNuaMeeV, ( C5-C10) aryl, arbitrarily substituted by one or several identical or different groups 8, phenyl, arbitrarily substituted by one or several identical or different CZ groups, (Sb -C16) arylalkyl, arbitrarily substituted by one or several identical or different CZ groups, 5 -10-membered heteroaryl, arbitrary

Kz substituted by one or more identical or different groups of KZ and 6-16-membered heteroarylalkyl, - arbitrarily substituted by one or more identical or different groups 8; 8 is selected from the group consisting of K 2, ve, va, substituted by one or several identical or different K2 or КР, -ОК2, substituted by one or several identical or different К2 or К?, -В(ОК2)»

ГИ -В(МеУВ2)5, "(СНо)т-в?, "СНУ, -О-(СНо)т-во, -8-(СНо)т в", -0-СНВев?, -о-сКУвУ , -O-(СНе)-е, -0-(СнНозСН(СН оз ЗЕ, -8-(СНЕ2)-В, -СШЦС(ОМН-(СНо)т-ве, -СК(ОМнА(СНАг) АК, -0-(СН.) н С(О)МНА(СН) where, -8-(СНо)т-С(ОМНА(СНо)т-в, -о-снве)-А-С(ОМНА(СНЕ 2 ) -K, 8iСНЕ 2) -С(ОМНА(СНВ 2)т-Бе, -МНА(СНао)т-ве, -Ммн-снв d) n-Бе, -МНИ(СНО)тв У, -М(СНо )tA r,

HF) -МН-С(0)-МН-(СН 2)т-ве, -МН-С(О)-(СНо)т-СНА В» and -МНА(СНо)т-С(0)-МН -(СН о)т-в;

F Every K? is independently selected from the group consisting of hydrogen, (C1-C6b) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl , 2-6-membered heteroalkyl, 3-8-membered cycloheteroalkyl, morpholine, piperazinyl, homopiperazinyl, piperidinyl, 4-11-membered cycloheteroalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl ;

Every VE? is a suitable group independently selected from the group consisting of 50, -OBB 9, (C1-C3) haloidoalkyloxy, -OSE3, -5, -589, -MU, -MOKU, -MAV2, halogen, -CEz, - SM, -MS, -OSM, -VSM, -MO, -MO», -M», -Maz, -B(O)89, -5(0)589, -(02089, -(O)MAUVe -( 02-Mv ve, -"ОБ(ОЖКУ, -05(0)589, -О5(0)2О89, -О5(О2МА В, бо -б(0)89, -С(0)Ов9, -сС(0 )MesVe, -S(MNIMAeVU, -S(MvUMesVe, -S(MON)a, -S(MONMveV, -oOS(OKU,

-oOsS(FOovU, -os(OMAevVe, -oS(MnuMesvVe, -oS(MvUMeove, -MNe(ozvvU, -Imves(olaVU, -MNesurovae, -IimvVas(OoDnOU, "(MNessuoma ve, (IM S(OMe ve, "(Ministry of Emergency Situations (MNuoMe SV and -(Mvas(Me 21, ev;

Each CO is independently K 2 , or, alternatively, each CO is taken together with the nitrogen atom to which it is attached to form a 5-8 membered cycloheteroalkyl or heteroaryl, which may include one or more of the same or different additional heteroatoms and can be replaced by one or more identical or different K? or suitable groups ve; each higher education institution independently represents a higher education institution; each t represents an independent integer from 1 to 3; and each n represents an independent integer from 0 to 3.

In the compounds according to the structural formula (I), I" and 12 independently of each other represent a direct bond or linker. Thus, as will be appreciated by those skilled in the art, the substituents K 2 and/or K 7 can be linked directly to by the corresponding nitrogen atoms, and alternatively be remote from the corresponding nitrogen atoms by a linker The nature of the linker is not critical and typical suitable linkers include, but are not limited to (C1-Cb) alkyldiyls, (C1-C6) alkanes, and (C1-Cb) heteroalkyldiyls, each of which may be substituted by one or more identical or different KZ groups, where KZ was previously defined in the structural formula (I). In a specific embodiment of the invention, each I" and 17 independently of each other is selected from the group that consists of a direct bond, (C1-C3) alkyldiyl, arbitrarily substituted by one or several identical or different KU, suitable for VE? or in groups and 1-3--ene heteroalkyldiyl, arbitrarily substituted by one or several identical or different KU, suitable VE? or in groups, where vo is selected from the group consisting of (C1-C3) alkyl, -OK 2, -F(O)OK2, (C5-C10) aryl, arbitrarily substituted by one or more identical or different halogens, phenyl, arbitrarily substituted by one or more identical or different halogens, 5-10-ene heteroaryl, arbitrarily substituted by one or more z. identical or different halogens, and b--lene heteroaryl, arbitrarily substituted by one or more he) identical or different halogens; and 2 and E?, which were previously determined for the structural formula (1).

Specific CO groups that can replace I" and 12 include -OC2, -C(O)OC2, phenyl, haloidophenyl, and 4-halidophenyl, where CO was previously defined for structural formula (1). "c zo In another specific embodiment implementation of the invention, each I1 and I2, independently of each other, is selected from the group consisting of methane-, ethane-, and propane-, each of which may additionally be monosubstituted by the group b"

E?, where VZ corresponds to the above definition. "--

In all the above-mentioned embodiments of the invention, specific B 2 groups that can be included in B? groups selected from the group consisting of hydrogen, (C1-C6b) alkyl, phenyl and benzyl. high school

In another specific embodiment of the invention, each I" and 12 has an acceptor bond such that (co)2,4-pyrimidinediamine compounds according to the present invention are compounds according to the structural formula (Ia): but) with Mk bno and next; there are more of them with: ryne ke - 50 including their salts, hydrates, solvates and M-oxides, where 22, 87, BZ and K9 represent the groups described earlier in the determination of the structural formula (I). Additional specific examples of the use of 2,4-pyrimidinediamine compounds in accordance with the present invention are described below. 7 represent the groups described earlier in the determination of the corresponding structural formulas (I) and (Ia) with the caveat that VC? is not di-C4,o-trimethoxyphenyl, C,4,5-tri(C1-C6)alkoxyphenyl or

F) ko 60 b5

K

22nd to 10th. "323 ok de, B", 22 and VZ correspond to the definition for B", B? and Z according to (U.S. Patent Mob235746), the disclosure of which is incorporated herein by reference. In the specific implementation of the first variant of the invention, VK?! represents hydrogen, halo-, unbranched or branched (C1-C6) alkyl, arbitrarily substituted by one or more identical or different to groups, hydroxyl, (C1-C6) alkoxy-, arbitrarily substituted by one or several identical or different phenyls or KK?" groups, thiol (-ZH), (C1-C6) alkylthio, arbitrarily substituted by one or several identical or different phenyls or groups, amino (-МН.), -МНК? or -МК76в?б; What? and KZ each independently represent unbranched or branched alkyl (C1-C6), arbitrarily substituted by one or more identical or different 25 groups; B??? is selected from the group consisting of haloido-, hydroxyl-, (C1-C6) alkoxy-, thiol, (C1-C6) Ha alkylthio, (C1-C6) alkylamino- and (C1-C6) dialkylamino-; and each 229 independently represents (C1-C6) alkyl, arbitrarily substituted by one or more identical or different phenyls or 2? groups or -С(О)Б2", where ВК?! represents (С1-Сб) alkyl, arbitrarily substituted by one or several identical or different phenyls or 25 groups.

In another specific example of implementation of the first option, B! represents methoxy, arbitrarily substituted by one or several identical or different haloido groups and/or each 222 and BZ independently of each other represent methyl or ethyl, arbitrarily substituted by one or several identical or different haloido groups. -

In the second embodiment of the invention, the compounds according to the structural formula (I) and (a) B2, B", in ta!i?. CI represent the groups described earlier in determining the corresponding structures (I) and (Iv), and I7 represents direct bond, and 9 is hydrogen, provided that VE? is not 3,4,5-trimethoxyphenyl, 3,4,5-tri(C1-C6) alkoxyphenyl or in 4 - - 22 what- ov s "23 yu ok - where is K7", V? and KZ are defined above in connection with the first embodiment of the invention. (Ce) In the third example of the implementation of the invention to 2,4-pyrimidinediamine compounds with the structural formula (I) and

Fo (Ia) do not include one or more of the following compounds:

Mm2,M4-bis(4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (KO70790);

Mm2,M4-bis(2-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (KO81166);

M2,M4-bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (KO88814);

Mm2,M4-bis(2-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (KO88815);

HF) M2,M4-bisphenyl-5-fluoro-2,4-pyrimidinediamine (KO91880);

Ф Mm2,M4-bis(3-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (K092788);

Mm2,M4-bis(3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (KO67962); in Mm2,M4-bis(2,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (KO67963);

Mm2,M4-bis(3,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (KO67964);

Mm2,M4-bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine (KO707153);

Mm2,M4-bis(2,4-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine (KO70791);

M2,M4-bis(3-bromophenyl)-5-fluoro-2,4-pyrimidinediamine (K008958); 65 M2,M4-bis(phenyl)-5-fluoro-2,4-pyrimidinediamine;

M2,M4-bis(morpholino)-5-fluoro-2,4-pyrimidinediamine; and m2,M4-bis|((3-chloro-4-methoxyphenyl)|-5-fluoro-2,4-pyrimidinediamine.

In the fourth example of the implementation of the invention, compounds with the structural formula (I) and (Ia) do not include compounds with the following structural formula (IB): p-!

Oov22

Fi u

A o M M M ov iv H nn de B?" represents (C1-C6) alkyl; and K27, K22 and KZ are defined above in connection with the first example of implementation of the invention.

In the fifth example of the implementation of the invention, the compounds with the structural formula (I) and (Ia) do not include the compounds described in Examples 1-141, US Patent Mob235746), the disclosure of which is incorporated into this document by reference.

In the sixth embodiment of the invention, the compounds of structural formula (I) and (34) do not include compounds defined by formula (1) or formula 1 (a) (US Patent Mob235746 (see, for example, the description from column 1, line 48 to column 7, line 49 and column 8, lines 9-36, information about which is included on the basis of reference c)).

In the seventh example of implementation of the invention, the compounds with the structural formula (I) and (Ia) do not include (o) compounds in which VE? is cyano- or -C(O) MNE, where B is hydrogen or (C1-Cb6) alkyl, if B? is replaced by phenyl; B" represents substituted or unsubstituted (C1-C6)alkyl, (C3-C8) cycloalkyl, 3-8-ene cycloheteralkyl or 5-15-ene heteroaryl; and E9-hydrogen.

In the eighth example of the implementation of the invention, the compounds with the structural formula (I) and (I34) do not include the compounds defined by the formula (I) and (X) (MUO 02/04429)| or any compounds disclosed in (MO 02/04429)|, the disclosure of which is incorporated herein by reference. "-

In the ninth example of implementation of compounds with structural formula (I) and (Ia), when 2? is cyano or -C(O)MNRE, where k- b - yl; 6. 2 are buckets and Her and Her cm hydrogen or (C1-Sb) alkyl; and KK" - hydrogen, then K- is different from the substituted phenyl group.

In the tenth example of implementation of the invention, the compounds with the structural formula (I) and (Ia) do not include (co) compounds in which each K2 and K7 is independently a substituted or unsubstituted ring of pyrrole or indole, which is connected to the rest of the molecule by means of a ring nitrogen atom.

In the eleventh embodiment of the invention, the compounds with the structural formula (I) and (Id) do not include "compounds defined in the formulas (I) and (IM) (US Patent No. 4,983,608) or any compound disclosed in |Patent

US Mo49836081, information about which is included in this document by reference. - c It is clear to specialists in this field that BC 2 and VC", which are part of formulas (I) and (Iz), can be the same or different, and can also vary widely. If К 2 and/or КЕ" represent optionally substituted rings, such as optionally substituted cycloalkyls, cycloheteroalkyls, aryls, and heteroaryls, one ring may be attached to the rest of the molecule by means of any available carbon or heteroatom. Additional 75 substituents can be attached to any available carbon atoms and/or heteroatoms. because In the twelfth example of realization of compounds of structural formula (I) and (Ia) 22 and/or 7 are additionally io) substituted phenyl or additionally substituted (C5-C15) aryl, provided that: - (1) if B is hydrogen, KV? cannot be 3,4,5-trimethoxyphenyl or 3,4,5-tri(C1-Cb) alkoxyphenyl; (2) if K2 is 3,4,5-trisubstituted phenyl, the substituents in the 3rd and 4th positions cannot be simultaneously methoxy) or (C1-Cb) alkoxy groups; or

Pr (3) if K 9U - hydrogen and KK? -(C1-C6) alkyl, (C3-C8) cycloalkyl, 3-8-membered cycloheteroalkyl or 5-15-membered heteroaryl, then KE? cannot be a cyano group. Alternatively, K? subject to the conditions described in connection with the first or second embodiments of the invention. An optionally substituted aryl or phenyl group can be attached to the rest of the molecule through any available carbon atom. Specific examples of additionally substituted phenyls include phenyls which are additionally mono-, di- or tri-substituted the same or different C groups, where KZ was previously defined in the description of structural formula (I) and is subject to the aforementioned conditions. If the co-phenyl is mono-substituted, the KZ substituent can be in the ortho-, meta- or para-position. When found in the ortho-, meta- or para-position, KZ is preferably selected from the group consisting of (C1-C10) alkyl, (C1-C10) 60 branched alkyl, -OK? additionally substituted by one or more identical or different groups, -0О-С(FOOK2, -0-(СН2)-С(ОО2, -КО)OKU, -0О-(СНо)в- MAU, -0О-СК(ОМАУВУ . ? and KO - defined earlier in the description of structural formula (I). In one example of the implementation of these compounds -MKUKU represents a 5-6-ene heteroaryl, which 65 arbitrarily includes one or more identical or different additional heteroatoms. Specific examples of such 5-6 --linen heteroaryls include, but are not limited to, the following: oxadiazolyl, triazolyl, thiazolyl,

oxazolyl, tetrazolyl and isoxazolyl.

In another example of implementation of these compounds -MKSKS is a 5-6-membered saturated cycloheteroalkyl ring, which additionally includes one or more identical or different heteroatoms. Specific examples of such cycloheteroalkyls include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, and morpholinyl.

In yet another example of the implementation of these compounds, each KU radical independently represents (C1-C6) alkyl and/or each -MVUVZ represents -MNE 2, where K2 is (C1-C6) alkyl. In one specific example, the short code is -"О-СН.-С(О)МНСН". In another specific example of the implementation of the invention, KZ is -OH.

In the case of disubstituted or trisubstituted phenyl KZ, the substituents can be in any combination of positions. For example, K substituents can be found in 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-, 2,34 -, 2,3,5-, 2 ,3,6-, 2,4,5-, 2,4,6-, 2,5,6- or 3,4,5-positions. In one exemplary embodiment of the compounds, which includes disubstituted phenyl, the substituents are at any position other than the 3,4-position. In another example of the implementation of the invention, they are in the 3,4 position. In one embodiment of compounds comprising 72 trisubstituted phenyl, the substituents are at any position other than the 3,4,5 or, alternatively, neither of the two substituents is at the 3,4 position. In another example, the substituents are in the 3,4,5 position.

Specific examples of KU substituents in such di- and tri-substituted phenyls include the various KU substituents described above in connection with ortho-, meta-, or para-substituted phenyls.

In another specific example of KZ, substituents suitable for replacing such di- and trisubstituted phenyls include (C1-C6) alkyl, (C1-C6) alkoxy, methoxy, halo, chloro, (C1-C6) perhaloidoalkyl, -SEZ, (C1 -C6) perhaloidoalkyl and -OSEZ groups. In preferred embodiments of the invention, such C substituents are in the 3,4- or 3,5-positions. Specific examples of preferred disubstituted phenyl rings include

Z-chloro-4-methoxy-phenyl, Z-methoxy-4-chlorophenyl, Z-chloro-4-trifluoromethoxy-phenyl, c

3-trifluoromethoxy-4-chloro-phenyl, 3,4-dichloro-phenyl, 3,4-dimethoxyphenyl and 3,5-dimethoxyphenyl, provided that: (1) if VE is one of the above phenyls, and each of 3 and K5 is hydrogen, then K? cannot be 3,4,5-tri(C1-C6) (o) alkoxyphenyl or 3,4,5-trimethoxyphenyl; (2) if Ge is 3,4-dimethoxyphenyl and each of VE: and 259 is hydrogen, then B" cannot be 3-(C1-C6) alkoxyphenyl, 3-methoxyphenyl, 3,4-di-(C1-Cb) alkoxyphenyl or 3,4-dimethoxyphenyl; (3) if K4 represents 3-chloro-4-methoxyphenyl and B? represents halo- or fluorine, and optionally VU "o is hydrogen, then KE? cannot be 3-chloro-4- (C1-C6) alkoxyphenyl or 3-chloro-4-methoxyphenyl; (4) if 7F is 3,4-dichlorophenyl and B is hydrogen, (C1-C6) alkyl, methyl, halo or chloro, and optionally, K 9 is hydrogen, then B? cannot be a monosubstituted phenyl in the para-position with a (C1-C6) alkoxy group, which is arbitrarily replaced by one or more identical or different B 9, -OH or -MVorVe C groups, where EE? and Ve are previously described in structural formula (I); and/or (5) BK and/or BK" is not 3,4,5-tri(C1-C6) alkoxyphenyl or co 3,4,5- trimethoxyphenyl, especially when B and 2 are each hydrogen.

In another example of the implementation of compounds that include trisubstituted phenyl, the latter has the formula: "1 :sh с Кк ;" - 32 and | ov ko - . cut (Se) (42) de V! is methyl or (C1-C6) alkyl; 32 hydrogen, methyl or (C1-C6) alkyl; and KZZ is a haloid group.

In the thirteenth example of the implementation of the invention, in compounds having the structural formula (I) and (Iv), B 2 and/or KK? represents an arbitrarily substituted heteroaryl. Typical heteroaryl groups, according to this thirteenth

HF) for example, contain from 5 to 15, and more typically from 5 to 11 ring atoms, and include one, two, three or about four identical or different heteroatoms or heteroatom groups selected from the group consisting of М, МН,

O, 5, Z (0) and (0). An arbitrarily substituted heteroaryl can be attached to the corresponding C2 or C4 nitrogen atom or linker I or I? through any accessible carbon atom or heteroatom, but is typically attached through a carbon atom. Additional substituents may be the same or different, and may be attached to any available carbon atom or heteroatom. In one example of the implementation of the invention, B? is not a bromo, nitro, trifluoromethyl, cyano, or -C(O)MNEK group where K is hydrogen or (C1-C6)alkyl. In another embodiment of the invention, if each of BK 2 and BK" is substituted or unsubstituted pyrrole or indole, then ring 65 is attached to the rest of the molecule through a ring carbon atom. In yet another embodiment of the compounds of this invention, including an arbitrarily substituted heteroaryl group, heteroaryl is unsubstituted or substituted with one to four identical or different KZ groups, where KZ is previously defined in structural formula (I). Specific examples of such optionally substituted heteroaryls include, but are not limited to, the following heteroaryl groups: with NN Ks s y sne SHA

At her ZV OK and SHIK, she taught sl z y and okon x ran p IY

And that ee en giy r; B

В В: DV oi. "ET sa tt, yo I, I nn SCHE I plun- Ih Z yakvinu iz zi te vy ik o I "A. V y. y t And I eh ! God k schy

That's what shen: PO varny nni Penn ate

Mo give this cloak - Veny snoe ay EE u ke A sezhio Jh dyin Jh

Net ince sii I DE so W Nm ot M Y a V a ZM ly Pe sonny ny KN ory in

Ov zno ani a M Shchi lie Eat Sey

SHE "SEE DY i Z sen AK s CHISHY tu NM ply caste enter tn: m ee M z y y her We y B s «Ш yГЯ DA sya 7 se sd y te- SN her y r ysy

I am her. you rent the house. And oh and: the nose of La same s

VK. Z z Si i ei tva S o san x ЖЖ cl. TE BEN t 1 : A. zh Eke Zh et p. du pan ke ME ev Y MDE ss nka

Echo shy re Vk sad te t Dok sho Ya iy vera 7 G V ME t TE ; . what about and || " (Te) zo at Shi ssha and banni s and F te yak and t zhy

MORE Dos Fest av. S M sei s her Z s

Ol Op PO torn o

Which ones: "Mg and SCHO syu; seg VK sni i svy ie; ia ho

Er zvn kny tona kA khz NIM with EE : M U azhvanykh i V What I lie Jhe nado omvu -- ad ze Dy i AJ pt Sho hop. "pezhr from sl B:

And Messeai y, Olyu y: NI Seya z lek: I zbu:

SYA sk pe tivy Eyakh V

G.I dig. spas KK suden pf sa. YN ryn se a Ye ey y s AY shk sii sgt-vschii ko - Her ey s i o Bezu chnyi Y z vo. sia as | «ha Te I: I tu s v Kok: zhi st kino shi p Coupons and a crane: y y th -5 I (ee) 7 B sno I - I g ev oy I g: g as Ek ey ; i o str, BV fer i s sk vn and already ve Ii NI zav IC ke. ех se ES BI - Still s s KO ne ud dent S.Y ten ts her | ro

Keks r soot fs SK cast IN TSN a

She and "M My what s THIS V s g osly IKK actions Pevroetkyakh ste s 1) ee Oh her pe o

AND | 7 ih ni ve I ko 60 b5 peva zv y pria" DV AB is Bosh - sv No Pn In s pai g: you

In b - whether I shi sho dn si Y, h

NOTHING ELSE KY Cain ya shcha kin , ve IV V izh sny: s p she a Kk: duh From own shchi ny trachea Beh end "Vady s SD, She sche ra KASH. t t: Ken nn ME

Ah NYA and Bu sht - : M. in Be; eat zak: y

EE, I, I, that - Vu, lys "KI y NYA Eh 2 ЖХОгЗ рр!

YAN NI and DE NI ZDA Y rations YO a . t sh se KY s rya PI od NI sla WHAT d "A se a SCHE Ks A, y in V Go zhe y ohbe SYA a ke 1 "A VE z pe os ke V osi pynyansk PE ak sb ke 6 ik Sh ha y y t y; pair g og A s Is so Y carry : not I rt y : y KZ il; r r i-i WHAT i same ey evil stand

WE MU I pen i Teh Zady i in Still with. Hey, harsh Kosai and o Dos seIe es Y sivy evil ЖНЯ лю НК cha в Still not those same Ye o A

DAYS ah ; kV a i u AK, Ye ta vne i i i k-;. sleep - CI; lo dya i se i zn She She sko ik y s V Ist NN a NI u tini z 1 i: s chi sia ZSh br aa Bach mn pen tny mon

ЖЖ I Vder not eaten: m still sia

I'm not that yet

I and oh pf "in de: set What Eh Z sech tok NYA: (SCHE ste Noya pre y sia t, EY flow. still chi and y Y SHE CHI yati I and she pk

WHAT and ; Yar sv nei ti - Beit still gy shcha ni I , IiE

DM Kn ta E TVA sya" ido p oz z sazhki b ia peyhy zo With what oh sya y (Se) gl Vi rech ped -du soryyny zh poder y y Ge"! maiden For h ts as much; her ONKO senyar NA and ste na zenirrnnya, chne zvaya o Vo z

I'm ED NOT Kafi under zd "l.YIV --

Shk Sho, u

Zo skh Ah y rok z Be Ya

KZ y t a sok an se B; o so with drinking Z. yayu neuritis Y t K ЖEK wound cancer

Me sah o PO EE R as o. same from sa Sai M ke: same tya tah What i 5 o Bin t i "

By ss Ne st day I rose - s «y soy shi her sleep o syak bas shsh

B Y --yy u "kiy ko "ly A ISCHE nya ushi i p KE i: "M voz chno M Eh sce t t i plroUkaneya zni: Re Mak p Syuovak: Mir, SHY kak r: kg tey -- DY B v is ZSHNe ke KA 0 lit losi t ol otr, Uya. o i what

Not Pi t Stevem B as. I know I and I yawned (22) more. and here

Well 4th B because b5

І и Не тел о сн Шче: УХЩ зак о ЗД и дл Шче су ; and Kt -oi tor piy ov that her and, vn ; a dream, che Reevny svi ii ie shchi l she

EE tni. Ann KA to 1 5 ШЧЧЩШ

Shchi Sha ery niy s oy She x spa: te and od

Still more; Bey ia and y: with that

MI Nizh i i and what SHY oi i YN t Z -y c. not odys-tya shag, and that I shk I t YOU Yainy I. t Z | | . more and | I am studying. 7 sha pek yk, si ply - olive t: ro kakiy Ir: i

KIK SCHO Iv tav 7 I and ShK" (o) is : (se) play: chi: Kot NN

KD iy Yar i- Zh, for " x z ta i -x h- «ory - still shchy Still like she I, I " da s sake s i Z shchy she. with st r V shchi i I di so i Op She OD

The same; MIA

CHE h 5 m as s p ha y tn - ; with" 1 heh. щ --Zy KE x Ж Ж slot riy is es zo 2 os NK y toru t ne nktya sp pai in zto t ZY Her BY: U so te i at r | that 51 and ho I tik di CHI yad -, no. z i ks Xia ey EK t -schi hv Bas nyu still tt r. tah. No | Y Mk i.

NI І b І where: ря р is an integer from one to three; each symbol ---independently represents a single or double bond;

HF) 85 is hydrogen or RU, where VZ is defined earlier for structural formula (I); t X is selected from the group consisting of CH, M and M -O0; each U is independently selected from the group consisting of 0, 5 and MN; in each U" is independently selected from the group consisting of 0, 5, 50, 505, ZOM, MN and MEZ"; each U? independently selected from the group consisting of СН, СН», О, 5, M, МН and met; 25 hydrogen or alkyl;

BZ is selected from the group consisting of hydrogen and a progroup, preferably the hydrogen or progroup is selected from the group consisting of aryl, arylalkyl, heteroaryl, K2, ВР-СВев?-о-сС(ОВ8, -СВev?-о- РО(ОК8», because -СН.-0о-РО(ОК8)5, -"СНо-РО(ОВ8)5, -С(0)-СВаве-М(СНаи)", -"СК2в2-о-сС( 0)-СВ2ve-M(SNai)", -"С(О)К8, -С(О)СЕз and

-F(0)-che8-s(ОВ8;

A is selected from the group consisting of 0, MH and Me 8: 28 is selected from the group consisting of alkyl and aryl;

WU, o, c" and "2 are each independently selected from the group consisting of alkyl, alkoxy, halogen, haloalkyl, aminoalkyl and hydroxyalkyl, or, alternatively, PE? apa B 79 and/or B"! and B 72 are taken together from a ketal; each 7 is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester, carbamate, and sulfonyl; then O is selected from the group consisting of "OH, OKU, -"MEUV2, "MNEZ9-с(ОВ8, "МНЕ 39-с(Фов8, -MEZ9-СНеЕ 0-в в, -МА39((СНо)т-в? and "М 39-с(0)- SNE 0-Megwe;

BZ and KO are each independently selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl; arylalkyl and MNE; and

What, 2? and B: defined above for structural formula (I). Preference is given to 9 substituents for C, which are selected from the C(IFOOVU, -O-C(ОВ8, -О-Р(ОХОВЗ)» and -Р(FOOV)» groups.

In one of the examples of implementation of the above-mentioned heteroaryls, as well as other 5-15-membered heteroaryls, according to this invention, each KZ is independently selected from the group consisting of BC 9, -MAgVe, "(СНО Me, -С( О)MAUKU, "СНо)t-С(О)MA Ne, -СШКК(FOONU, "(СНо)т-С(О)ОВ9 and -(СНо)т-ОВУ, where т, КО and КЗ are defined above for structural formula (1).

In a specific example, BU and/or BO is selected from the group consisting of B 2 and (C3-C8) cycloalkyl, arbitrarily substituted by one or more identical or different hydroxyl, amine or carboxyl groups. high school

In another example of the implementation of the aforementioned heteroaryls, each KZ? is a hydrogen atom, (C1-C6) carbon chain, including methyl, ethyl, isopropyl, cycloalkyl group, including cyclopropyl, o cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, ; where x-1-8, -SNOSOMNMe, - | (22).

In another embodiment of the aforementioned heteroaryls, the aromatic ring linkage is in the 5 or 6 position. It is believed that any of K2 or KE? can use the heteroaryl groups described in this application.

In the fourteenth example of realization of compounds of structural formulas (I) and (Ia), EC? and E7 each, independently of each other, is an arbitrarily substituted phenyl, aryl or heteroaryl, provided that: - c (1) if I" represents a direct bond and K9 (and optionally KO) is hydrogen, then K? cannot be "» 3,4,5-trimethoxyphenyl or 3,4,5-tri(C1-Cb) alkoxyphenyl; " (2) if every And! " and And? represent a direct connection, B. 9 - hydrogen and VE? -haloido-group, then B? and B? cannot be 3,4,5-trimethoxyphenyl or 3,4,5-tri (C1-Cb) alkoxyphenyl at the same time; so 15 (3) if K 7 is 3-methoxyphenyl or 3-(C1-C6) alkoxyphenyl and BK 2 is 3,4,5-trisubstituted phenyl, then the substituents in the 3rd and 4th positions cannot to be methoxy or (C1-Cb) alkoxy groups at the same time; io) (4) if VE? represents substituted phenyl and KZ is hydrogen, then E? cannot be a cyano-or -С(О)МНЕ group, where В - - hydrogen or (С1-Сб) alkyl; and/or (5) if each K2 and K7 is independently substituted or unsubstituted pyrrole or indole, then the pyrrole or indole is attached to the rest of the molecule via a ring carbon atom. Alternatively, EC 2? subject to the conditions described in

Fo connection with the first or second examples of implementation of the invention.

In this fourteenth example of the implementation of the invention B 2 and K7 substitutes can be the same or different. Specific, optionally substituted phenyl, aryl, and/or heteroaryl include those illustrated above in the twelfth and thirteenth exemplary embodiments.

In the fifteenth example of implementation of compounds with structural formulas (I) and (Ia), including the described i) examples of implementation from the first to fourteenth, B ZU is hydrogen and BE? represents an electronegative group. As recognized by those skilled in the art, electronegative groups are atoms or groups of atoms that have a relatively high tendency to attract electrons to themselves. Specific examples of electronegative groups, 60 according to the fourteenth implementation example, include, but are not limited to the following: CM, -MS, -MO»5, halo-, bromo, chloro, fluoro, (C1-C3) haloidoalkyl, (C1-C3) perhaloalkyl, (C1-C3) fluoroalkyl, (C1-C3) perfluoroalkyl, -SEZ, (C1-C3) haloidoalkyl, (C1-C3) perhaloidoalkyl, (C1-C3) fluoroalkyl, (C1-C3) perfluoroalkyl, -OSEz, -С(О)К2, -С(О)OKe, -С(О)СЕз and -С(О)ОСЕз. In a specific example, the electronegative group is an electronegative group containing a halogen, for example -OCE3, -CE3, bromine, chlorine or fluorine group. In another concrete example of EC? is fluorine, provided that this compound cannot be the compound described in the third embodiment of the invention.

In the sixteenth example of implementation of the invention, compounds with structural formulas (I) and (Ia) correspond to compounds having structural formula (IB): 13 5 12 ia и и М ; . KE 14 | Y U, re . and | 11

E м M M Kk as well as their salts, hydrates, solvates and M-oxides, where each B"! 72, B! and B!!! independently of each other is selected from the group consisting of hydrogen, hydroxide, (C1- C6b) alkoxy and -MK UC; and 25, 25 and KO are defined earlier in the description of structural formula (I), with the proviso that if each B 13, E5 and K5 is hydrogen, then B" and B" cannot be at the same time methoxy, (C1-Cb) alkoxy or (C1-Cb) haloido-alkoxy groups.

In the seventeenth example of the implementation of the invention, compounds with structural formulas (I) and (Ia) correspond to the structural formula (Is): c do o, 4 Fe so

E incl. in in? F

N N | )y c as well as their salts, hydrates, solvates and M-oxides, where

B" is selected from the group consisting of 5-10-membered heteroaryl and 3-hydroxyphenyl;

B is E or -CE"5; and

ВZ is -«О(СНо)т-Ко, where т and КУ were defined earlier for the structural formula (I). In a specific implementation example, KZ is -0-СНо-С(О)МН-СН" and/or КЕ" is a heteroaryl, according to the thirteenth implementation example.

In the eighteenth example of implementation of the invention, compounds with structural formulas (I) and (I4) include - c any compound selected from Table 1, which inhibits the signal transduction cascade of E-receptors, the activity of Zuk-kinase, the signaling cascade of receptors dependent on Zuk kinases or cell degranulation, as determined by ip"» migo studies, provided that the compound is not a compound that is excluded in the above third embodiment and/or other examples. In one particular example, such compounds have an IC of about 2 µmole or less according to the results of the measurement of cell degranulation in the process of analyzing IP myo, as described in

Go! section "Examples".

In the nineteenth example of the implementation of the invention, the compounds with the structural formulas (I) and (Ia) include where any compound selected from Table 1, which inhibits the cascade of Esu K1 or Esu K1 receptors with an IC of 20 μmol according to the results of the measurement of degranulation cells and myo, as described in the "Examples" section, provided that this compound is not a compound that is excluded in the above third example of implementation of the invention and/or other examples. b In the twentieth example of implementation of the invention, compounds with structural formula (Ia) are compounds where KE? is selected from the group consisting of x ,;

F) t - 60 23 k with b5 in ke ky , d te 4 ov Z Y Z : - - ko Z g g ; , rve, and a; you i, where i 2 x ke i z i | and 4 kg 4 g in 7 and te, 7 and te; in ki vi, 2 x ke i ze z i; 4 kg 4 g in 7 and te, 7 and te; What are you and your friends? who

WE and | i - kg 4 g ha i wa 1 re) zo Kk with 7 and with 7 and 7 b» ky di vy or 2 in ke se 4 ok Z

From here ; (ge) 4 kg 4 g in the 7th and the, 7th and the;

Р", бе, бе, Р", Бе, ВУ - correspond to the above values; ВК? is a fluorine atom; КО is "y c a hydrogen atom and each B?! independently represents halogen atoms or alkyl, optionally substituted by one or "with several identical or different halo groups; KE? and BZ represent, each independently of each other, "a hydrogen atom, methyl or ethyl, optionally substituted by one or several identical or different halo groups; each t is independently an integer from 1 to 3, and each n is independently an integer from 1 to 3.

In the twenty-first example of the implementation of the invention, the compounds with the structural formula (Ia) are (ог) compounds, where В" is н; where ВЗ and КО correspond to the above indicated о я - г. | b

KE! "so 50 --4- (Y M -- o H with a value of 52 and include each independently hydrogen atom, and B? is a phenyl group substituted by one or several identical KU groups, or, where ВZ has the above values. In 60 E E /j b5 with one particular case, if KE? represents a phenyl group, then one or more C is selected from halogen or alkyloxy groups. Otherwise, the phenyl group is di- or tri-substituted by one or more by the same short-circuit groups,

In the twenty-second example of implementation of the invention, compounds with the structural formula (Ia) are compounds where B" is and K2 is a phenyl group substituted by one or

C With several identical short-circuit groups. In one particular case, one or more CZ is selected from a halogen or an alkyloxy group. Otherwise, the phenyl group is di- or tri-substituted with one or more identical KZ groups.

In the twenty-third example of the implementation of the invention, the compounds with the structural formula (Ia) are compounds where KE" represents a phenyl group substituted by one or more identical KZ groups, where ВК? represents where ВЕ has the above value. In a specific implementation , phenyl group B" | х г Most s o w z is di- or tri-substituted with the same or different halogen atoms. In another BC implementation? is a co-phenyl group monosubstituted by a halogen atom. In one case, short circuit? is a hydroxyalkyl group. In other cases, the hydroxyalkyl group can change to an ether group, carbamate, etc. b"

In the twenty-fourth example of implementation of the invention, compounds with the structural formula (Ia) are compounds in which КЕ" is , where КЗЗ has the above value, and B?

With c g | M so in . - c : : : : 8 35 x with a phenyl group substituted by one or more identical KU groups. In one specific case, K" represents a hydrogen atom or an alkyl group. In another case, the phenyl group K2 is di- or trisubstituted by the same or different KZ groups, and in particular by halogen atoms.

In the twenty-fifth example of the implementation of the invention, the compounds with the structural formula (Ia) are compounds in which B" represents; where КЕ? has the above value and K? represents t I Zhe x z Yar m /4

F with p with itself 10, where is KE? and KO have the above values and each independently

F) Kk

Gi 60 I r

НН и о н includes a hydrogen atom. In one case, KZZ is a hydrogen atom or an alkyl group, such as methyl, and B C 65 and B" are alkyl groups, such as methyl groups.

In the twenty-sixth example of implementation of the invention, compounds with the structural formula (Ia) are compounds in which B" is a disubstituted phenyl group substituted by the same or different BU groups, and БЕ? is , where ВЗ has the above value. In some in some cases, the phenyl group; mon

Not in : r M

And, and is: replaced by a halogen atom and an alkyloxy group, for example, a methoxy group. In specific examples of implementation of the invention, VZ? represents a hydrogen atom, an alkyl group, such as a methyl group, or a hydroxyalkyl group. In /5 In some cases, the hydroxyalkyl group can change to an ether group, carbamate, etc.

In the twenty-seventh example of implementation of the invention, compounds with structural formula (Ia) are compounds in which o is | ,; and about enter Knrya sch v o n o . not (Se) ; or where VZ and Co. 3. | -В- - | i so is 40 a , chn, 8 ;" " have the values indicated above, and K? represents a phenyl group substituted by one or more B 8 groups. In one particular case, BO represents a hydrogen atom or an alkyl group. In another case, the phenyl group B 2 is a di- or trisubstituted by the same or different KKZ groups, and in particular by halogen atoms or CO Н - the 7. z o y (42)

In the twenty-eighth example of implementation of the invention, compounds with the structural formula (Ia) are compounds in which B" is where U, m and each B? independently have the above-mentioned m

b B

F. st K ry r ka ' | Where are 2 and 60? is For ; where VZ has the above value. In one

M. U

In the case of implementation of the twenty-eighth example of the invention relative to 27, U" represents oxygen, 2 is MH, and one or more KZ? or B" components represent an alkyl group, in particular a methyl group. In some cases of the twenty-eighth example of implementation of the invention, two groups B 9, which are included in the composition of B 7, form a heme-dialkyl component, in particular, a heme-dimethyl component adjacent to the MH group, denoted by 19 o - In other cases of implementation of the twenty-eighth example of the invention ' r ' Me e M

N Me

E in relation to K?, 29? represents a hydrogen atom or an alkyl group, in particular a methyl group. high school

In the twenty-ninth example of the implementation of the invention, the compounds with the structural formula (Ia) are compounds in which B 7 is and ; where КО and КО"О have the above indicated (o)

IS

0 Zo is | -- that;

M

9) n --

IS; c z5 Values or represent a substituted phenyl group. In one case, the phenyl group is di- or tri-substituted with one or more identical KZ groups. In particular, the phenyl group may be di- or tri-substituted by one or more halogen atoms, which may be the same or different. B? in the twenty-ninth example of the implementation of the invention is ;l where KZZ has the above-mentioned « p - s KI m---na5 . a pu / lay M » so ' zations 35 2 values. In one case of the twenty-ninth example of implementation of the invention, K of K- is not a methyl group. In another case of the twenty-ninth example of the implementation of the invention, B 2 is either - or that; zy x 4) i ny sht -O 4- ch u M (F): IY ek u or i 60 b5 o - i x 9 nm she - ch u m 70 : -N i lyk /

M or : M .

In the thirtieth embodiment of the invention applicable to the first to twenty-ninth examples, o represents a halogen atom such as fluorine, and KU represents a hydrogen atom.

Combinations of the above examples of implementation of this invention from the first to the thirtieth are also specifically described.

Those skilled in the art will appreciate that the 2,4-pyrimidinediamine compounds described herein may include functional groups that may be masked by progroups to form prodrugs. Such prodrugs, of course, but not always, are pharmacologically inactive until they are converted into an active medicinal form.

Indeed, many of the active 2,4-pyrimidinediamine compounds listed below in Table 1 include procomponents capable of hydrolysis or other cleavage under the conditions of use. For example, ester groups usually undergo acid-catalyzed hydrolysis to form the initial carboxylic acid if they are in the acidic conditions of the stomach, or undergo alkali-catalyzed hydrolysis if they are in the basic environment of the gut or blood. Thus, when prescribed for oral use, 2,4-pyrimidinediamines that include esters can be considered prodrugs of the corresponding carboxylic acid, regardless of whether the ester has a pharmacologically active form. at

Listed in Table 1, numerous 2,4-pyrimidinediamines of this invention, containing a complex ester, demonstrate activity in the form of a complex ester - in the form of prodrugs.

In the proposed prodrugs of this invention, any available functional component can be (Ce) masked by a progroup in order to form prodrugs. Functional groups in 2,4-pyrimidinediamine compounds that may be masked by a progroup for incorporation into a procomponent include, but are not limited to, amines (primary and secondary), hydroxyls, sulfonyls (thiols), carboxyls, and the like. In practice, a large number of progroups are known, suitable for masking such functional groups in order to obtain procomponents that are cleaved under the desired conditions of use. All these progroups, individually or in combinations, can be included in the prodrugs of this invention. co

In one illustrative example, the prodrugs of the present invention are compounds of structural formula (I) in which BEU and BU may represent a progroup in addition to previously defined alternative variants. "

Replacement of hydrogen atoms attached to M2 and M4 in 2,4-pyrimidinediamines of structural formula (1) by substituents adversely affects the activity of the compounds. However, as will be assessed by specialists, these nitrogen atoms - c can be included in procomponents, which under the conditions of use are split with the formation of h 2,4-pyrimidinediamines of the structural formula (I). Thus, in another example, prodrugs according to the present invention are compounds according to structural formula (11): e? so ko) ro s 50

I: In fact, I told her ZM M you me and rea 2

F)

KkZz including their salts, hydrates, solvates and M-oxides, where

In, VU, in", 85 | and And? defined earlier for structural formula (1); and 60 V? and VC" each, independently of each other, is a progroup. Specific examples of progroups in this embodiment of the invention include, but are not limited to (C1-C6) alkyl, -"C(O)CH z, -C(OMNAZE, and - B(0),225, where K36 (C1-Cb) is alkyl, (C5-C15) aryl and (C3-C8) cycloalkyl.

In prodrugs with the structural formula (I), the substituents can be selected according to the first to twenty-sixth implementation examples given above for the compounds of the structural formula (I) and (Ia) or combinations of such examples.

Those skilled in the art will appreciate that many of the compounds and prodrugs of the present invention, as well as the various exemplary compounds specifically described and/or illustrated herein, may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and/or optical isomerism. For example, the compounds and prodrugs of the present invention may include one or more chiral centers and/or double bonds and, as a result, may exist as stereoisomers, such as double bond isomers (eg, geometric isomers), enantiomers, and diastereomers. and mixtures thereof, such as racemic mixtures. As another example, the compounds and prodrugs of the present invention can exist in several tautomeric forms, including the enol form, the cone form, and mixtures thereof. Since various names, formulas and structures of compounds within the scope of the specification and claims of the invention can represent only one of the possible tautomeric forms, 7/0 forms of conformational isomerism, optical isomerism or geometric isomerism, it should be considered that this invention covers any tautomeric forms, forms of conformational isomerism, optical isomerism and/or geometric isomerism of compounds or prodrugs having one or more of the advantages described in this application, as well as mixtures of these various isomeric forms. In cases of limited rotation about the 2,4-pyrimidinediamine core structure, atropic isomers are possible and are also specifically included in the compounds of this invention.

Moreover, those skilled in the art will appreciate that if the list of alternative substituents includes members that, due to valency or other reasons, cannot be used to replace a specific group, then only those members from the list that are suitable for replacing a specific group should be used groups For example, skilled practitioners will appreciate that while all listed alternatives for B? can be used to replace an alkyl group, certain substituents such as -O cannot be used to replace a phenyl group. It should be borne in mind that only possible combinations of substituent groups can be used.

Compounds and/or prodrugs of the present invention may be identified by their chemical structure or their chemical name. If the chemical structure and the chemical name conflict, the chemical structure is decisive for the identification of the particular compound. urine

Depending on the nature of the various substituents, the 2,4-pyrimidinediamine compounds and prodrugs of the present invention may be in salt form. Such salts include salts suitable for pharmaceutical use ("pharmaceutical salts"), salts suitable for veterinary use, and the like. Such salts may be derived from acids or bases as is well known in the art.

In one of the implementation examples, the salt is a pharmaceutically acceptable salt. Of course, pharmaceutically acceptable salts are salts which substantially retain one or more of the desired pharmacological functions of the parent compound and which are suitable for human use. Pharmaceutically acceptable salts include acid addition salts formed with inorganic or organic acids. Inorganic acids suitable for the formation of "-- pharmaceutically acceptable acid addition salts" include, but are not limited to, the following: hydrohalic acids "for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid,

Acid, phosphoric acid, and the like. Organic acids suitable for the formation of pharmaceutically acceptable acid addition salts include, but are not limited to, the following: acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, alkylsulfonic acids - with (e.g. , methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, and 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (for example, benzenesulfonic acid, "" 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, cycloalkylsulfonic acids (for example, camphorsulfonic acid), 4-methylbicyclo|2,2,21-oct-2-ene-1-carbo xylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, laurylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like. where Pharmaceutically acceptable salts also include salts formed upon replacement of an acidic proton present in the starting compound by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion), an ammonium ion, or as a result of coordination with an organic base (e.g. , ethanolamine, diethanolamine, triethanolamine, M-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine, etc.).

Fo 2,4-pyrimidinediamine compounds according to the present invention, as well as their salts, can also have the form of hydrates, solvates and M-oxides, as is well known in practice.

Methods of synthesis

The compounds and prodrugs of this invention can be synthesized by a variety of methods using commercially available starting materials and/or starting materials prepared by conventional synthetic (F;) methods. Various methods that can be used to synthesize the 2,4-pyrimidinediamine compounds and prodrugs of this invention , described in (US Patent No. 5958935), to which reference is made in this application. Specific examples describing the synthesis of numerous compounds and prodrugs according to the present invention, as well as their intermediates, are given in the "Examples" section. All compounds with structural by formulas (1), (Ia) and (II) can be prepared by simple modification of these methods.

A variety of possible synthetic methods that can be used to synthesize the 2,4-pyrimidinediamine compounds of the present invention are described below in Schemes (I)-(XI). In Schemes (1I)-(XI), compounds with similar numbers have a similar structure. These methods can be used to synthesize prodrugs that correspond to the structural formula (I).

In one exemplary embodiment, the compounds may be synthesized from substituted or unsubstituted uracils or thiouracils, as illustrated in Scheme (I) below:

ЯВ is B s ves nekosheokiv for vyh i PC

PI y, nich sia on vn shield

KI ayu kubut day 5 ІВ. river ac reno svasovnatankyh essay Meshchi svya i 5 SHIKH t Vkvnkya M y; what are you doing? s - she Ye F "and the same with shob shi from 16 so

In Scheme (I) 2, 27, 25, 259, 17 and I? defined earlier for structural formula (I), X is a halogen (for example, E,

SI, Vg or I) and M and U, each independently of each other, are selected from the group consisting of O and 5. By

In scheme (I), uracil or tisouracil 2 is dihalogenated in the 2nd and 4th positions with the help of a standard "halogenating agent PHOX" (or another standard halogenating agent) under standard conditions to form (C with 2,4-bishalidopyrimidine 4. Depending on the substituent P", in pyrimidine 4, the halide in the C4 position reacts more strongly with c nucleophiles than the halide in the C2 position. This difference in reactivity can be used for the synthesis of "2,4-pyrimidinediamines of the structural formula (I) by carrying out the reaction between 2,4-bishalo-pyrimidine 4 with one equivalent of amine 10 to form 4H-substituted-2-halo-4-pyrimidinamine 8, followed by amine b to form the 2,4-pyrimidinediamine of structural formula (I). 2M,4M-bis(substituted)-2,4-pyrimidinediamines 12 and 14 can be obtained as a result of the reaction of 2,4-bishalido-pyrimidine 4 with an excess of compounds 6 or 10, respectively. ki In most cases, the C4 halide is more reactive towards nucleophiles, as shown in Scheme - However, as will be recognized by experienced specialists, the nature of the EC substitute? can change this reactivity. "c 20 For example, if E? represents trifluoromethyl, then a 50:50 mixture of the compound 4M-substituted-4-pyrimidinamine 8 and the corresponding 2M-substituted-2-pyrimidinamine is obtained. Regardless of the nature of the RU substituent, the regioselectivity of the reaction can be controlled by choice of solvent and other synthesis conditions (such as temperature), as is well known in the art.

The reactions depicted in Scheme (I) can occur faster when the reaction mixtures are heated in microwaves. In this case, the following conditions can be used: heating to 17523 in ethanol for 5-20 min in

F! Smith's reactor (manufactured by Regzop! Spetizig) in a hermetic tube (under a pressure of 2O0bar).

Starting materials uracil or thiouracil 2 can be purchased commercially or prepared using standard organic chemistry tools. Commercial uracils and thiouracils that can be used as starting materials in Scheme (I) include, but are not limited to, the following: uracil (Aiagisp bo Mo13,078-8; SAB Kedivigu 66-22-8); 2-thio-uracil (AlYidgispn Mo11,558-4; SAB Kedivigu. 141-90-2); 2,4-dithiouracil (Aidgisp Mo 15,846-1; SAB Kedivigu 2001-93-6); 5-octouracil (Spet. Zotsgsez IpG! 2000; SAB Kedivzigu 6214-65-9); 5-azidouracil; 5-aminouracil (AiYadgisp Mo85,528-6; SAB Kedizigu 932-52-5); 5-bromouracil (Aiagisp

Mo85,247-3; SA Kedivigu 51-20-7); 5-(trans-2-bromovinyl)-uracil (Aidgisn Mo45,744-2; SAB Kedivigu 69304-49-0); 5-(trans-2-chlorovinyl)-uracil (CA5 Kevdizig 81751-48-2); 5-(trans-2-carboxyvinyl)-uracil; because uracil-5-carboxylic acid (hydrate of 2,4-dihydroxypyrimidine-5-carboxylic acid; Algiss Mo27, 770-3; CA

Kedizigu 23945-44-0); 5-chlorouracil (AiYagismo 222, 458-8; SA Kedivigu 1820-81-1); 5-cyanouracil (Spet. Zoshgsev, 2000; SAB Kedivigu 4425-56-3); b-ethyluracil (Aliagisp 823, 0044-86; SAB Kedivigu 4212-49-1); 5-ethenyluracil (SAZ Kedivigu 37107-81-6); 5-fluorouracil (AiYidgispy Mo85, 847-1; SABZ Kedivigu 51-21-8); 5-iodouracil (AlYidgispy Mo85, 785-865; SAB Kedizigu 696-07-1); 5-methyluracil (thymine; AiYdgis Mo13,199-7; CA5

Kedizigu 65-71-43; 5-nitrouracil (AiYidgispy Mo85, 276-7; SAB Kedivigu 611-08-5); uracil-5-sulfamic acid (Spet. Botsgsez Ipg! 2000; SAB5 Kedizigu 5435-16-5); 5-"trifluoromethyl)-uracil (Algisp Mo22, 327-1; SA Kedivigu 54-20-6); 5-(2,2,2-trifluoroethyl)-uracil (CA Kedivigu 155143-31-6); 5-"(pentafluoroethyl)-uracil (SAB Kedivigu 60007-38-3); b-aminouracil (Aidgis Moab5O60-6; SA Kedizigu, 873-83-6) uracil-b-carboxylic acid (orotic 7/0 Acid; Aiigisn Mo0-840-2; SAZ Kedizigu 50887-69-9); b-methyluracil (Aiygisp Me 011, 520-7; SAZ Kedivngu 626-48-2); uracil-5-amino-β6-carboxylic acid (5-aminoorotic acid; AiYagispy Mo19, 121-3; SAB5 Kedizigu

Mo7164-43-4); b-amino-5-nitrosouracil (b-amino-2 4-dihydroxy-5-nitrosopyrimidine; AiYagisn Mo27, 689-8; SAZ

Keadivigu, 5442-24-0); uracil-5-fluoro-6-carboxylic acid (5-fluoroorotic acid; AlIdhispy Mo42, 513-3; CA5

Keadizigu 00000-00-0); and uracil-5-nitro-6-carboxylic acid (5-nitroorotic acid; AlYidgispy Mo18, 528-0; SAB5 /5 Kedivigu 600779-49-9). Additional 5-, 6-, and 5,6-substituted uracils and/or thiouracils can be purchased from

Sepega! Ipiegteadiaies oi Sapada, Ips., (Edmonton, Alberta, Canada) (mmliu.depegaiiipiegtedia(ev.sot) and/or

IpFiegspit, France (mlmlm.ipiegspit.sot), or can be prepared using standard methods. Below are a large number of references to textbooks that outline the relevant synthetic methods.

Amines b and 10 can be purchased from commercial sources or, alternatively, can be synthesized, 2o using standard methods. For example, the corresponding amines can be synthesized from nitro precursors using standard chemical methods. Specific examples of reactions are given in the "Examples" section. See also: Modei, 1989, Rgasiisa! Ogdapis Spetivigu, Adaizop U/ezieu I opdtap, tsa. apa dopp Umieu 5 5opv, Ips.).

It is known from practice that in some cases amines b and 10 and/or substitutes BE? and/"or BU on uracil or thiouracil 2 may include functional groups that require protection during synthesis. The specific form of urine of any of the protecting groups used will depend on the specificity of the functional group to be protected and will be clear to those skilled in the art. on the selection of appropriate protecting groups, as well as synthesis strategies for their attachment and removal, can be found, for example, in the work of Greene and Woots, "Protecting Groups in

Organic Synthesis", 3rd edition, John Wiley & Sane, New York, 1999. references given in this edition (hereinafter "Sgeepe 8 UUshi8")).

A specific example of implementation of Scheme (I), in which 5-fluorouracil (Aiagisp Mo32, 937-1) is used as a primary material, is given below in Scheme (Ia): "- c

Scheme (Ia) so and du E ЩЪ

Fi: rf to knock out social workers; I equiv H with H « 9 2 s ;» 10 1 equiv. 6 In (og) re ROS EFi in BF t al oo s zm 2's surplus vch and -k N z n z n z 5 11 (Se) 4 10 surplus

F)

E - 1 » and 60 species nn with n 13

In Scheme (Ia) -K2, VU, I and I? correspond to the values previously determined for Scheme (I). According to Scheme (Ia), 5-fluorouracil Z is halogenated with ROSI Z to form 2,4-dichloro-5-fluoropyrimidine 5, which then 65 reacts with the amine residue 6 or 10 to form M2,M4-bis-substituted 5 -fluoro-2,4-pyrimidinediamine 11 or 13, respectively. Alternatively, the asymmetric 2M,4M-disubstituted-5-fluoro-2,4-pyrimidinediamine U can be obtained by the reaction of 2,4-dichloro-5-fluoropyrimidine 5 with one equivalent of amine 10 (to form 2-chloro-M4- substituted-5-fluoro-4-pyrimidinamine 7) and then with one or more equivalents of amine 6.

In another embodiment, the 2,4-pyrimidinediamine compounds of this invention can be synthesized from substituted or unsubstituted cytosines as shown in Schemes (IA) and (IB), below:

Scheme (PA) with t ve

S acylation, in v v, te yun silylation tosho a Mn ROHU me M 70 6 ' z 1 - 656 -k shre z A v a A, . zmyuch NM EMO skh vm: M zo NM Z7M TO 0 (other halogenating and other agents) . r) 22 24 6 - s, Hn

Conclusion from under the protection of Geo "MORE

Te" aa "sht le dok 10 5 pil x '

ИЗ у s Where and | ria Die Ran "M 1 So s y shi she mm: M ?

H with H with w (8) (0)

Scheme (PV) (Se) ve ve p Ge) e v 5 g t. MN 10 tya MN ROXa V tk - o pdv CHO p niinn vv r p : ME сх ; ; I: tea 4 2 Catalysis for zvy "(Other halogenating in J se

M M's; account 6 t I» M : o agentn) Shu Y ih "x acids 400 2 bases 23 25 (ge) inhalation

M i in "- s g" g ve ve

In her S Hn v

KE ' '

DISTRICT SMOKE dy cMm 7" in M o p NO pn VK so 270 (anshi and leads t. all smt t

But I'm in the Workshop 2) Take out But from NN

Kkz 7 29 under protection (d - p 50 In Schemes (PA) and (IV) B, 27, 25, 9, 17, 12 and X correspond to their previous values in Scheme (I), and RO is a protective group. Referring to In Schemes (IA), the C4 exocyclic amine of cytosine 20 is first protected by the appropriate protecting group RO to form the Ш-protected cytosine 22. For specific advice on the protecting groups used in this context, see Mogbgiddep apa Kyi-Ropiepl, 2001, Naparook oh

Mysieozide Zupipevzii, doip UMpPeu 5 Bopv, MU, year 1-631|. Protected cytosine 22 is halogenated at the C2 position using a standard halogenation reagent under standard conditions to form 2-chloro-4M-protected-4-pyrimidinamine 24. Reaction with amine 6 and subsequent deprotection of the C4 exocyclic amine and reaction with amine 10 leads to to the formation of 2,4-pyrimidinediamine, which corresponds to the structural formula ko ().

Alternatively, as shown in Scheme (IB), cytosine 20 can react with amine 10 or protected 60 amine 21 in order to form Ш-substituted cytosine 23 or 27, respectively. These substituted cytosines can then be halogenated as previously described, deprotected (in the case of the M4-substituted cytosine 27 ) and reacted with amine 6 to form 2,4-pyrimidinediamine of structural formula (1).

Commercially available cytosines that can be used as starting materials in Schemes (IA) and (PV) include, but are not limited to, cytosine (Aiagisp Mo14, 201-8; SAZ Redivigu 71-30-7); M'-acetylcytosine bo (Aiagisp Mo37, 791-0; SAZ Kedivigu 14631-20-0); 5-fluorocytosine (Aiagisp Mo27, 159-4; CA5 Kedivigu 2022-85-7);

and 5-trifluoromethyl)-cytosine. Other cytosines that can be used as starting materials in Schemes (PA) can be purchased from Sepeg! Ipiegtediaiez of Sapada, Ips. (Edmonton, Alberta, Canada) (soap.depegaiipiegteadiaev.sot) and/or Ipiegspit, France (m/mly.ipiegspit.sot), or may be prepared,

Using known standard means. References to textbooks containing relevant synthetic methods are provided below.

In yet another embodiment, the 2,4-pyrimidinediamine compounds of this invention can be synthesized from substituted or unsubstituted 2-amino-4-pyrimidinols, as illustrated in Scheme (III) below:

How did ZV eat?

In eq with 8 V: : Because ke V

WHAT | and BO ех с сах ши Данж ебнноетто и Ме я ЧИ С Я ni Шы ше В зо t ше si - (8) г воху s

I

I would

BA Ya ze and s

WE t Ha so give her in : Kesh

Me IN nn shi she ceiera « dO Ko she. YAVI Y he nin: with Sy o)

That і і і і Щ Ко BV z

In Scheme (PI), 2, 7, 5, 9, 17, 12 and X correspond to the values in Scheme (I), and 7 represents a substitution group, which will be described in more detail in Scheme IM below. According to Scheme (I), 2-amino-4-pyrimidinol ZO reacts with amine 6c (or selectively protected amine 21) to give M2-substituted-4-pyrimidinol 32, which is then halogenated as described above to give M2 -substituted-4-haloido-2-pyrimidinamine 34.

Additional loss of protection (for example, when using protected amine 21 in the first stage) followed by reaction with amine 10 leads to the formation of 2,4-pyrimidinediamine of structural formula (I). Alternatively, pyrimidinol 30 may react with acylating agent 31.

Suitable commercially available 2-amino-4-pyrimidinols 30 that can be used as starting materials in Scheme (I) include, but are not limited to, 2-amino-6-chloro-4-pyrimidinol hydrate (Aiagisp

Mod4702-8; SABZ Kedivigu, 00000-00-0) and 2-amino-b-hydroxy-4-pyrimidinol (AiYiIdgis Mo ABO40-1; SAZ Kedivigu 56-09-7). Other 2-amino-4-pyrimidinols 30 that can be used as starting materials in Scheme (I) 29 are available from Sepegas. IpiegtediaFez oi Sapada, Ips., (Edmonton, Alberta, Canada)

GF! (soap. depegaiiipiegtteadieyew.sot) and/or Ipiegspit, France (mlmlm.ipeigspit.sot) or can be prepared using standard methods. References to textbooks that describe the relevant synthetic methods are given below.

Alternatively, the 2,4-pyrimidinediamine compounds of the present invention can be prepared from 60 substituted or unsubstituted 4-amino-2-pyrimidinols as illustrated in Scheme (IM), below: b5

Scheme (IM) in ? to vo v, ko v vich, v 5, sakh 6 vesashti 44 sa

BUT it is

BM: Ton tya shi m te og 10 dostmoEvm'mostv z z Н N z Нn 40 42 () /5 In Scheme (IM) K2, VK", B", 29, I and 12 correspond to the previous definitions in Scheme (I) , and 7 represents a substituted group.In Scheme (IM), the C2-hydroxyl of 4-amino-2-pyrimidinol 40 is more reactive toward nucleophiles than the C4-amino to the extent that reaction with amine 6 leads to the formation of M2-substituted-2 ,4-pyrimidinediamine 42.

The following reaction with compound 44, which includes a well-substituted group 7 or amine 10, leads to the formation of 2,4-pyrimidinediamine, which corresponds to the structural formula (I). Compound 44 can include virtually any substituent that can be substituted with the C4-amine of M2-substituted-2,4-pyrimidinediamine 42. Suitable substituents 7 include, but are not limited to halogens, methanesulfonyloxy (mesyloxy; "OMv") .

Substituted 4-amino-2-pyrimidinol, which is used as a starting material, can be obtained on a commercial basis or synthesized using standard means. References to textbooks that (o) describe the relevant synthetic methods are provided below.

In yet another embodiment, the 2,4-pyrimidinediamine compounds of the present invention can be prepared from 2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines as illustrated in Scheme (M) below: "c (2)

Scheme (U) «-- with 6 in ves 5 DE 1 In 8 4 o nn i FA . what 2 and I sm mn, to Mo: vn, « 50 6 og 31 -v

I 52 in s: Kk 5 (:z" - ZY 2. 1 ve zn

N z n so (6 bi ko e ro y vo Z z 5 C more; Ffi - and KK. s-m and 2

ГИ Н z va Be 25 In Scheme (M) 22, 7, 25, 29, 17, 12 and X correspond to the previous definitions in Scheme (I), and 7 represents the group defined in Scheme (IM). In Scheme (M), 2-amino-4-chloropyrimidine 50 reacts with amine 10 to form 4M-substituted-2-pyrimidinamine 52, which then reacts with compound 31 or amine b to form co 2,4-pyrimidinediamine of structural formula (I ). Alternatively, 2-chloro-4-amino-pyrimidine 54 can react with compound 44 and amine 6 to form a compound of structural formula (1). 6o Examples of commercially available pyrimidines 50 and 54 that can be used as starting materials in Scheme (M) include, but are not limited to, the following: 2-amino-4,6-dichloropyrimidine (Aidhispy Mo

A4860-1;, SAB Kedivigu 56-05-3); 2-amino-4-chloro-b-methoxy-pyrimidine (AiYidgis Mo51, 864-6; SAB Kediviu 5734-64-53; 2-amino-4-chloro-b6-methylpyrimidine (AiYdgis Mo12, 288-2; SAB Kediviu 5600-21-5); and 2-amino-4-chloro-b-methylthiopyrimidine (AIdgisp Mo A4600-5; SAB Kedivigu 1005-38-5). Additional pyrimidine-based starting materials can be purchased from Sepegai companies! Sapada, Ips., (Edmonton,

Alberta, Canada) (mulu.depegaiipiegtteadiaiev.sot) and/or Ipiegspit, France (m/mlu.ipeigspit.sot) or can be prepared using standard means. References to textbooks that provide relevant synthetic methods are provided below.

Alternatively, 4-chloro-2-pyrimidinamines 50 can be prepared as illustrated in Scheme (Ma):

Scheme (Ua) b

In the 5th year - MN Kat vo. re - re

МН сМмНн у n 2 2 M: мн,

Gee! WITH

AND

53 51

AgSOZN ve vo

B in the village

V. ikh Ros o it' Z ay - To; che sim, OM Si h 2 "MN. 3 Y o "se 50 F 55 "--

In this Scheme (Ma) 2? and KZ represent the groups described earlier in the definition of structural formula (I). In Scheme (Ma), dicarbonyl 53 reacts with guanidine to form 2-pyrimidinamine 51. Reaction with peracids of the type (co)t-chloroperbenzoic acid, trifluoroperacetic acid or a complex of hydrogen peroxide with urea leads to the formation of M-oxide 55, which then halogenated to form 4-chloro-2-pyrimidinamine 50.

The corresponding 4-haloido-2-pyrimidinamines can be obtained using appropriate halogenation reagents. "

In yet another embodiment, the 2,4-pyrimidinediamine compounds of this invention can be prepared from substituted or unsubstituted uridines, as illustrated in Scheme (MI) below: - c ;» so ko - (Se) (42)

Ф) ko 60 b5 y b Ж I Sh no, sce: vk, s «y ey ke Jany 5 70 ШЯ ee s YASCHY zi: pa: MAN g she ya na: рн b. I from o she J. t 7 i

Kt satyny Eat U t ta te i g» y Kay i: i-y naya u | I don't want to blow the grain, and I'm the 2nd one r: Ma She and sec re I x ssh pi: Mk no She I Kk si UNo y: chn mo she Movy I Still. t NYA PAETYNNNKT z Z va: yiv t F

She and NN no I sha F ssh vi and shk sny sho - shi I she write SHY sch

Because yes

From co

In Scheme (m) 22, B", 25, 25. 17, I? and X represent the groups previously described in the definition of Scheme (I), and the indicator of the degree of RO represents the protective group described in connection with Scheme (IV) . According to Scheme (MI), uridine 60 has a reactive C4 center such that reaction with amine 10 or protected amine 21 leads to the formation of "

Ma-substituted cytidine 62 or 64, respectively. An acid-catalyzed deprotection reaction (deprotection) of 7 s of M4-substituted 62 or 64 (if PO represents an acid-labile protecting group) also leads to the formation of M4-substituted cytosine 28, which can subsequently be halogenated at the C2 position and can enter reaction with "" amine 6 in order to form 2,4-pyrimidinediamine according to structural formula (1).

Similarly, cytidines can also be used as starting materials, as illustrated

In the Scheme (MINE) below: so co - (Se) (42) co 60 b5 sv more so

Kok / v i tk -k av sia y

Cent oyu it is more important zhk IN and 1 gi t va

I with - B (8)

Vb. ше Z зо В Ай выш Ше ше де де ана я ШЕ ой F

Kaya or

In Scheme (mi), B2, K7, 25, 29, 17, 12 and X represent the groups described earlier in the description of Scheme (I), and the PO degree indicator represents the protective group described above. In Scheme (MI), similarly to uridine 6bO, cytidine 7/0 also has a C4 reactive center; thus reaction with amine 10 or protected amine 21 leads to the formation of co

Ma4-substituted cytidine 62 or 64, respectively. These cytidines 62 and 64 are then processed as above for

Schemes (MI), in order to form 2,4-pyrimidinediamine, which corresponds to the structural formula (1).

Although Schemes (MI) and (MII) exemplify ribosyl nucleosides, one skilled in the art will appreciate that the corresponding 2i-deoxyribonucleosides and 2,3'-dideoxyribonucleosides can be used, as well as nucleosides comprising sugar or sugar analogues, excluding riboses.s c Numerous uridines and cytidines that can be used as starting materials in Schemes (MI) and (MI) are well known in the art and include, but are not limited to, the following: 5-trifluoromethyl-2'-deoxycytidine (Spet. "" Zotsgsez Mo AVSK RO7669; SA Kedivigu 66,384-66-5); 5-bromouridine (Spet. bZotsgsez Ipg! 2000; SAB Kedivigu 957-75-5); 5-iodo-2'-deoxyuridine (AlYagisp Mo1 -775-6; SABZ Kedivigu 54-42-2); 5-fluorouridine (Aliagispn Mo32,937-1; 435 SA Kedivigu 316-46-1); 5-iodouridine (Aliagisn Mo85,259-7; SAB Kedivigu 1024- 99-3); 5-"trifluoromethyl) uridine

Go! (Spet. botsgsev p! 2000; SAB Kedivigu 70-00-8); 5-trifluoromethyl-2'-deoxyuridine (Spet. Botsgsevs IH! 2000;

SAB Kedivigu 70-00-8). Additional uridines and cytidines that can be used as starting materials in Schemes (MI) and (MII) can be purchased from Sepega! Ipiegtedia(ez oi Sapada, Ips., (Edmonton, Alberta, - Canada) (mil. depegaiiipiegteaideaevz.sot) and/or Ipiegspit, France (mmly.ipiegspit.sot). or can be prepared using standard means. Links to textbooks, which give relevant synthetic methods are given below.

The pho 2,4-pyrimidinediamine compounds of the present invention may also be synthesized from substituted pyrimidines, such as chloro-substituted pyrimidines, as illustrated in Schemes (MI) and (IX) below:

F) ko 60 b5

Scheme (UP) si nyu (- these ' . WHAT A и U g

AK u u ov we pev p ve M x M M iya A ektsha N Z Nn 82 va

AND! si I nm Tv dr 6 Ex ' 10 there is also y

Kit kno sy yem smt trazymy mah p ym z z N Y z H 75 80 81 85

Oh no, it's not my fault

Nooz no: 83

Skenmiihu

I bis dya 7 Viko, zho F s-7ya and y

I sha i a -- b i i i neck vn o

ZO world g ; them and live them or tn, tya shoyu ter There is scha? complete and most valuable Z

WHAT! ши шк шчи ту « I ate what 7 yah I did not ts I Sn tyu same

Pong U Ku NO: I ha pa Ei Y

Go! en Z also B. p dk In Schemes (MIII) and (IX) 22, VU, I, B2, and B2 represent the groups described earlier in the determination of the structural formula - (), and "Ag" represents the aryl group. According to the Scheme (MI!), the reaction of 2,4,b-trichloropyrimidine 80 (AiYagispy ZhT5,620-0; so 20 SABAZ7b4-01-0) with amine b leads to the formation of a mixture of three compounds: substituted pyrimidine mono-, di-, and triamines 81, 82 and 83, which can be separated and removed by high performance liquid chromatography (HPLC) or other conventional means. Mono- and diamines 81 and 82 can further react with amines 6 and/or 10 to form M2, M4, Hb-trisubstituted-2,4,6-pyrimidinetriamines 84 and 85, respectively.

M2,M4-bis-substituted-2,4-pyrimidinediamines can be prepared in a manner similar to that shown in Scheme (MI) using 2,4-dichloro-5-methylpyrimidine or 2,4-dichloro-pyrimidine as starting materials. In this case, the mono-substituted pyrimidine amine corresponding to compound 81 is not formed. Instead, a reaction

F, directly leads to the formation of M2,M4-bis-substituted-2,4-pyrimidinediamine.

Kkz According to Scheme (IX), 2,4, 5,6-tetrachloropyrimidine 90 (Ayagispy Mo24,671-9; SAB Mo 1780-40-1) reacts with excess amine b to form a mixture of three compounds: 91, 92, and 93 , which can be separated and isolated using HPLC or other conventional means. As illustrated above,

M2,M4-bis-substituted-5,6-dichloro-2,4-pyrimidinediamine 92 can be further reacted at the Cb halide position with, for example, nucleophilic agent 94 to form compound 95. Alternatively, compound 92 can be converted to

M2,M4-bis-substituted-5-chloro-6b-aryl-2,4-pyrimidinediamine 97 by Suzuki reaction (5igiki). 2,4-pyrimidinediamine 95 can be converted to 2,4-pyrimidinediamine 99 by reaction with Vp3ZPN. 65 Those skilled in the art will appreciate that the 2,4-pyrimidinediamines of the present invention, synthesized by the above or other well-known methods, can also be used as starting materials and/or intermediates to synthesize additional 2,4-pyrimidinediamine compounds .

A specific example is given in Scheme (X) below:

Scheme (X) pe vo , 5 8 vo dk- m and (8) nЬmKe Kk ; pe M i y or rve 4 o / : "zy MV MEVI TI og zy Men vy mn zn zn 100 104 8 v? v vo is v re m" de» Ge! and Shi sa I 102 | Cho i -- t 2 1 ne AK A oda ven mn Za Mnv" in "M 4 M 2 their juice H with H

And 1 106 be

In Scheme (X), 7, ER, 25, 17 and Be represent the groups described earlier in the determination of structural formula (1).

Each KU independently represents K -, and can be the same or different from the given K 2. According to Scheme (X), carboxylic acid or ester 100 can be transformed into amide 104 by reaction with amine 102. In amine 102, the group The CU can be the same or different from the CU of the acid or ester of 100. Similarly, the carbonic acid ester 106 can be converted to the carbamate 108.

A second specific example is illustrated in Scheme (XI) below: (Ce)

Scheme (XI) F is ve "-- v, zho (SNa)a5 Va Vi xx sa 112 na s v AJ i vve 77770 knocked out U "dove disc attstschY chaAKk in dv M so

НН with НН зн 110 1 - res sve y "vh Y aksha y y y"? ; rai ch Uy y 112 2 m r --0 "mesve 2 | -o mabde -32 ah nya he a i in Kk M M M 45. K I M M z Nn noz pn 118 so 116 o In Scheme (X) 7, 5, 25, 12? and KO represent the groups described earlier in the definition of structural formula (I). According to Scheme (XI), amide 110 or 116 can be converted to amine 114 or 118, respectively, by reduction of borane with boranemethylsulfide complex 112. Other suitable reactions for the synthesis of 2,4-pyrimidinediamine compounds from 2,4-pyrimidinediamine starting materials are readily apparent. for specialists in

AI of this field.

Although many of the synthetic schemes discussed above do not reflect the use of protecting groups, it is clear that in some cases the substituents B, B", B, B5, 1" and/or I? may include functional groups that require protection. The exact properties of the protecting group employed will depend, among other things, on the nature of the functional group being protected and the reaction conditions in the particular synthetic scheme, as will be apparent to those skilled in the art. Advice on choosing the protective group and mechanisms for kz attachment and elimination suitable for a particular application can be found, for example, in Sgeepe 8. MUtsiv (see above). 60 Prodrugs corresponding to structural formula (II) can be prepared using a conventional modification of the above methods. Alternatively, such prodrugs can be obtained as a result of the reaction of a protected 2,4-pyrimidinediamine of structural formula (I) with a suitable progroup. The conditions for carrying out such reactions and the conditions for deprotection of the reaction product to form prodrugs corresponding to formula (II) are well known. 65 A large number of methods for the synthesis of pyrimidines, as well as the starting materials described in Schemes (1I)-IX), are known in the literature. For specific advice, the reader can refer to the following sources: |Vhom/p, Yu. 9., "Te

Rugitidipev", ip Tye SPetivigu oi Neegosussis Sotrotspi5z, Moishte 16 (Uueizzbegdeg, A., Ey), 1962,

Ipiegesiepse Rybiizpege, (A Oimiviop oi Odopp o MMieu 5 Bopv), Mem MZhogk ("Vgozhmp 1"); Vgomup, O. 9., "Te

Rugitidipev", ip Te SPetivigu oi Neijegosusis Sotrotspavz, Moiishte 16, Zirrietepi | (U/eizzbregdeg, A. apa

Tauyug, E. S, Ea.), 1970, UMieu-Ipiegvsiepse, (A Oimiviop oi doip UMPeu b Bopv), Mem HogKk (Vhom/p 11"); Vhom/p, OH. U., "Te Rugitidipev", ip Te Spetivigu oi Nei(egosusis Sotrotspaz, Moishte 16, Z!irrietepi II (U/eizzregdeg, A. apa

Tauyug, E. S, Ed.), 1985, Ap Ipiegzsiepse Rybiisayop (oip UMiPeu 5 ope), Mem Mogk ("Vgomup PI"); Vgomp, O. U., "Te Rugitidipev" ip Te Spetivigu oi Neiegosussis Sotrotspaz, Moishte 52 (UUeizzbregdeg, A. apa Tauiog, E. S,

Ed), 1994, dopp o MUyeu 5 Bopv, Ips., Mem MogKk, pp. 1-1509 (Vgomup IM"); Keppeg, S. MU. apa Toda, A.,, ip 70 Neiegosussis Sotrotspaz, Moitste b, ( EiIdepiviy, MK. S, Ei), 1957, supplement on UMMpeu, Mem/ MogK, SParieg 7

SRugitidipev"); Radtsietse, I. A., Rgipsiriev oi Modegp Neiegosusiis SNPetivigu, 1968, MU. A. Vepiatip, Ips.,

Mem Mogk, pp. 1-401 ("Ogashi! vupipevziv" pp. 313, 315; "Rugitidipe zupipeviv" pp. 313-316; "Atipo rugitidipe zupipevziz" pp. 315); doshie, U. A., Miiyiv, K. apa tiy, o. R., Nefegosusiis Spetivigu, ZYA Edaiop, 1995, Spartap apa

Naiyi, Gopdop, OK, years 1-516; Mogrgiddep, N. apa Kip-Ropiepg, S, Naparook oiMisieovide Zupipeviv, dopyp UMyeu 5 75 Zopv, Mem Moi, 2001, pp. 1-631 ("Rgoiesiop oi rugitidilez Bu asuiayop" pp. 90-91; "Zyuiaip oi rugitidipev" years 91-93); doshie, 9. A., Miiyiv, K. apa Ztiyb, 0. E., Neegosusiis Spetivigu, action of Eaiiop, 2000, ViasKmeiY

Zsiepse, TSY, Ohoga, OK, years 1-589; apa Sotrgepepsime Ogdapis Zupipevziv, Moishtevs 1-9 (Ttovi, V. M. apa

Nietipo, I., Ed.), 1991, Regdatop Rgezv, Ozhkhgoga, OK).

Inhibition of signaling cascades of ES receptors

The active 2,4-pyrimidinediamine compounds of this invention inhibit signaling cascades of Es receptors, which lead, among other things, to cell degranulation. For example, these compounds inhibit the signaling cascades of Eseki and/or Esu KI receptors leading to degranulation of immune cells such as neutrophils, eosinophils, mast cells and/or basophils. Mast and basophil cells play a central role in allergen-induced disorders, including, for example, allergic rhinitis and asthma. As shown in Fig. 1, under the influence of allergens, which can be, among other things, pollen or parasites, B-cells, activated by I/-4 (or 1-13) and other (5) mediators, synthesize allergen-specific IDEs antibodies in order to proceed to the synthesis of a specific antibody of the IDE class. These allergen-specific IDEs bind to Ese CIs with high affinity. After antigen binding, Ese K1-bound IDEs are cross-linked and the IDE receptor signal transduction pathway is activated, which leads to cell degranulation and the subsequent release and/or synthesis of a set of chemical messengers and e) (mediators), including histamine, proteases (such as tryptases and chymases), lipid mediators such as b leukotrienes (e.g., TC4), platelet-activating factor (PARE), prostaglandins (e.g., POI2), and a series of cytokines, including TME-o, , 1I-- 4, 1-13, 1-5, 1-6, 1-8, ZMOZE, MESS and TOB-D Fr. The release and/or synthesis of these mediators from mast and/or basophil cells is the cause of early and late responses caused by allergens, and is directly related to the processes occurring in the direct direction, which lead to a long-term inflammatory state. with

The molecular processes on the path of signal transduction by PsEsh receptors, which lead to the release of preformed mediators through degranulation and the release and/or synthesis of other chemical mediators, are well known and depicted in Fig.2. As shown in Fig.2, Ese KI is a heterotetrametric receptor consisting of I9E-binding alpha subunits, beta subunits, and two gamma subunits (gamma homodimer). 70 Cross-linking of Ese Ki-bound (DE) with the help of multivalent binding agents (including, for example, IdE-specific allergens, or anti-I (DE antibodies, or fragments) causes rapid association and "c activation of bho- dependent up-kinase I. up phosphorylates the tyrosine-based immunoreceptor activation motif (MAIIBT) on intracellular beta- and gamma-subunits, which leads to the recruitment of additional up to the beta subunits and 5uk-kinase to the gamma homodimer. receptor-bound kinases activated by 75 intra- and intermolecular phosphorylation phosphorylate other components of the pathway, such as Vic kinases, coG AT, and phospholipase C-gamma RI C-gamma).Activated RI C-gamma initiates pathways that leading to protein activation

KkZz kinase C and mobilization of Ca ions, both of which are required for degranulation. Cross-linking of Es K1 also activates three major classes of mitogen-activated protein kinases (MAPs), ie, EKK1/2, OMK1/2, and p38.

Activation of these pathways is important in the transcriptional regulation of pro-inflammatory mediators, such as TME-y and (se) I/-6, as well as lipid mediators leukotriene CA (I TC4).

Fo Although not depicted in the drawing, the Esu CI receptor signaling cascade is believed to share some common elements with the Esu CI receptor signaling cascade. Importantly, similar to Esi CI, Esu CI includes a gamma homodimer that is phosphorylated and recruits 5UC, and as in the case of Esi CI, activation of the Esi signaling cascade

CI leads, among other things, to degranulation. Other Es receptors that have a gamma homodimer and can be regulated by active 2,4-pyrimidinediamine compounds include, but are not limited to, Eso, CI, and Esu CI. (F, The ability of the 2,4-pyrimidinediamine compounds of the present invention to inhibit signaling cascades of Es receptors can be easily determined or confirmed as a result of immunoassays. Assays confirming inhibition of Es are

CI-mediated degranulation, given in the "Examples" section. In one typical assay, cells 60 undergoing Es Ki-mediated degranulation, such as mast cells or basophils, are first grown in the presence of 1-4, stem cell factor (SCF), 1I-6, and IDE to increase Es Ki expression. exposed to the test compound 2,4-pyrimidinediamine of the present invention and stimulated by anti-IdeE antibodies (or, alternatively, an IDE-specific allergen). After incubation, the amount of a chemical mediator or other chemical agent released and/or synthesized as a result of the activation of the Ese CI signaling cascade can be determined using standard means and compared to the amount of the mediator or agent,

released from control cells (such as cells stimulated but not exposed to test compounds). The concentration of the test compound that results in a 5095 decrease in the measured amount of the mediator or agent compared to the control cells is equal to the ISbo of the test compound. The origin of the mast or basophil cells used in the quantitative assay will depend, in part, on the desired use of the compounds, as will be apparent to those skilled in the art. For example, if the compounds are to be used for the treatment or prevention of some disease in humans, a convenient source of mast or basophil cells is a human or other animal that is considered a suitable or known clinical model of such disease. Thus, depending on the specific application, mast or basophil cells can be obtained from a variety of animal sources, ranging from lower mammals such as mice and rats, to dogs, sheep, and other mammals commonly used in clinical trials, to higher mammals such as monkeys, chimpanzees, and great apes, and humans. Specific examples of cells suitable for performing ip myo assays include, but are not limited to, rodent cells or human basophils, rat leukemia basophilic cell lines, primary mouse mast cells (such as 7/5 mouse bone marrow-derived mast cells "BMMS" ) and primary human mast cells isolated from umbilical cord blood (CMC) or other tissues, such as lung tissue. Methods of isolation and cultivation of these types of cells are well known or given in the "Examples" section, see, for example, YuOeto et al., 1999, Suioteigu 36(4):340-348 and patent application Mo10/053,355, filed Nov. 2001, the disclosure of which is incorporated herein by reference).

Of course, other types of immune cells that degranulate after activation of Ese CI signaling cascades can also be used, including, for example, eosinophils.

Those skilled in the art will agree that quantification of a mediator or agent is not required. The only requirement is that the particular mediator or agent be released and/or synthesized as a result of the initiation or activation of the Es receptor signaling cascade. For example, as shown in Fig. 1, the activation of the signaling cascade Ese KI in mast and/or basophilic cells leads to numerous events that occur in the direct c direction. For example, the activation of the signaling cascade of EC leads to the immediate release by means of degranulation (from 1 to 3 minutes after the activation of the receptor) of a variety of preformed chemical mediators or mediators and agents. Thus, in one exemplary embodiment, identified mediators or agents may be specific to granules (ie, be present in granules rather than in the cytoplasm of the cell). Examples of granule-specific mediators or agents that can be quantified to determine and/or (Ce) confirm the activity of a 2,4-pyrimidinediamine compound of the present invention include, but are not limited to, the following: granule-specific enzymes such as hexosaminidase, tryptase, and granule-specific components, such as histamine and serotonin. Assays for the quantification of such factors are well known and, in many cases, commercially available. For example, the release of tryptase and/or hexosaminidase can be quantified by incubating cells with cleavable substrates that fluoresce after cleaving and quantifying the fluorescence produced by conventional methods. Such cleavable fluorogenic substrates are commercially available. For example, the fluorogenic substrates 27-biu-Pho-Agao-AMS (where 7-benzyloxycarbonyl and AMOS-7-amino-4-methylcoumarin; VIOMOY. Kezgzeagesy I arogayogiev,

Ips., Riutoshi Meeyipo, RA 19462, Sayaiod Mo. P-142) and 2-AIa-yuv -Aga-AMS (Eplute Zuvietv Rgodisiv, a dimiviop oi ISM Vioteais!v, Ips., Himeptpoge, CA 94550, Saiaiyud Mo. AMSO-246)) can be used to "determine the amount of released tryptase Fluorogenic substrate 4-methylumbelliferyl-M-acetyl-. r z c -Yub-glucosaminid (Zidta, 5 Iotsiv5, MO, Saiiosd 69585) can be used to count the amount of a released hexosaminidase. Histamine release can be quantified using a commercially available enzyme-linked immunosorbent assay (ELISA), such as the EHI5A histamine assay by Mo.

IM2015 (VesKtap-Sotspeg, Ips.). Specific methods for quantification of tryptase, hexosaminidase, and histamine release are provided in the Examples section. Any of these quantitative assays can be used to (ee) determine or confirm the activity of the 2,4-pyrimidinediamine compounds of this invention.

Referring again to Fig. 1, degranulation is only one of several responses initiated by the Ese CI signaling cascade. In addition, the activation of this signaling pathway leads to the de pomo synthesis and release of cytokines and chemokines, such as II-4, I-5, 1-6, TME-o, 1-13 and MIR1, and the release of lipid mediators such as "c 20 leukotrienes (ITS4), platelet activation factors (RAE) and prostaglandins. Accordingly, the activity of the 2,4-pyrimidinediamine compounds of the present invention can be assessed by determining the amount of one or more 1) mediators released and/or synthesized by activated cells.

Unlike the granule-specific components described above, these "late stage" mediators are not released immediately after the activation of the EsekiI signaling cascade. Therefore, when carrying out the quantitative determination of these late-stage mediators, it is necessary to take into account that the activated cell culture is grown for a time sufficient for the synthesis (if necessary) and the isolation of mediators that are subject to

IF) quantitative determination. In general, RAC and lipid mediators, such as leukotriene C4, are released io) 3-30 minutes after activation of Esse KI. Cytokines and other mediators of the late stage are released approximately 4-8 hours after the activation of Ese KI. The length of time that corresponds to specific mediators is known to those skilled in the art 60 . Specific tips and quantitative analyzes are provided in the "Examples" section.

The amount of a specific isolated late-stage mediator can be determined using any standard method. In one example implementation, the quantity can be determined using an EI ISA analysis.

EIIZA sample kits suitable for determining the amount of TME o, 11/-4, 1/-5, I/-6 and/or released

І/-13, can be purchased at Viozotsgse Ipiegpayopa!І, Ips. Satagyo, SA 93012 (see, for example, catalog numbers КНОСЗ011, КНСО042, КНСОО052, КНСОО61 and КНСО132). EGI5A kits, suitable for determining the amount of leukotriene C4 (I TS4) released from cells, can be purchased at Sautap Spetisai

So., App Agbrog, MI 48108 (see, for example, catalog number Mo. 520211).

Typically, the active 2,4-pyrimidinediamine compounds of the present invention will have an IC concentration of 20 µmol or less relative to the Es of KiI-mediated degranulation and/or a level of release or synthesis of mediators of 20 μmol or less as measured by the ip myo as described above or in the "Examples" section.

Of course, those skilled in the art know that compounds exhibiting low IC values, such as 1Ωmole, 1μmole, 10Onmole, 1Onmole, Tnmole, or even lower, are particularly useful.

Those skilled in the art will also agree that the various mediators described above may cause 70 different adverse effects or may exhibit different levels to the same adverse effect.

For example, the lipid mediator TC4 is a potent vasoconstrictor that is approximately 1,000 times more vasoconstrictive than histamine. In another example, in addition to mediating atopic or Type I hypersensitivity reactions, the cytokine may also induce tissue transformation and cell proliferation.

Thus, despite the possibility of using compounds that inhibit the release and/or synthesis of one of the 7/5 previously described chemical mediators, those skilled in the art will agree that compounds that inhibit the release and/or synthesis of most, or even all of the previously described mediators, will undoubtedly find specific applications given their ability to ameliorate or completely suppress most or even all of the adverse effects caused by individual mediators. For example, compounds that inhibit the release of all three types of mediators, granule-specific, lipid, and cytokine, are useful for treatment or prevention

Immediate hypersensitivity reactions of Type I, as well as their accompanying chronic symptoms.

Compounds of the present invention that are capable of inhibiting the release of more than one type of mediator (eg, granule-specific or late-stage mediator) can be identified by determining the IC 50 against a representative mediator of each class using the various IP mic assays described above. (or other equivalent IP migo analyses). For the compounds proposed in this invention, which p

Capable of inhibiting the release of more than one type of mediator, typical IC values of less than 20 μmol for each type of mediator under study are typical. For example, a compound for which the IS 5o value is o

1mmol on the release of histamine (IS histamine and 1mol on the synthesis and/or release of ITS4-leukotriene (ISvoi7c8), inhibits the release of both the immediate (granule-specific) mediator and the mediator of the late stage. zo In another specific example, the compound, for which IS vu'riptase equals 1Ommol, ISvobTsYA equals Immol and what

ISvo!-4 equals Imkmol, inhibits the release of immediate (granule-specific), lipid and cytokine mediators. Although the above specific examples use the IC 50 of one representative mediator of each class, those skilled in the art will agree that the IC values of most, or even all, of the mediators that make up one or more classes can also be obtained. For specialists in the given field, it will be obvious the number and identity of the mediators for which the values of so should be established

ISvo for a certain compound and its application.

Similar quantitative analyzes can be used to confirm the inhibition of signaling cascades initiated by other Es receptors, such as Eso, CI, Esu CI and/or Esu CIII, with the usual modification.

For example, the ability of compounds to inhibit Esu signal transduction by CI receptors can be confirmed using "assays similar to the above, except that the Esu Ki signaling cascade is activated, for example, as a result of incubation of db cells with allergen-specific Id, or antibody instead of DE and allergen-specific IDE or antibody. Those skilled in the art are familiar with suitable cell types, activating agents, and agents required for quantification to confirm inhibition of other ES receptors, such as ES receptors that are part of the gamma homodimer.

A particularly useful class of compounds includes 2,4-pyrimidinediamine compounds that inhibit the release of immediate (se) granule-specific mediators and late-stage mediators with approximately equivalent IC values. By approximately equivalent, it is meant that the ICs for each type of mediator differ from each other by no more than a factor of 10. Another particularly useful class of compounds includes the 2,4-pyrimidinediamine compounds which - inhibit the release of immediate granule-specific mediators, lipid mediators and cytokine mediators with approximately equivalent ICs. In a specific example, these compounds inhibit the release of the following mediators with approximately equivalent IC values: histamine, tryptase, hexosaminidase, II-4, 1-5, 1-6, 1-13, TMERo and

GI and TS4. Such compounds are particularly useful for, inter alia, ameliorating or completely suppressing both early and late-stage responses associated with atopic reactions or Type I immediate hypersensitivity reactions.

Ideally, it is desirable that the ability to inhibit the release of all desired types of mediators is inherent in a single compound. However, it is possible to name mixtures of compounds that provide the same result. For example, iF) the first compound, which inhibits the release of granule-specific mediators, can be used in combination with the second

With a compound that inhibits the release and/or synthesis of cytokine mediators.

In addition to Ese KI or Esu KI degranulation pathways described above, degranulation of mast and/or basophilic cells 60 can be caused by other agents. For example, ionomycin, which is a calcium ionophore that bypasses the early signal transduction mechanism of the cell's Ese CI or Esu CI, directly induces a calcium influx that initiates degranulation. As shown in Fig. 2, activated RI Su initiates pathways leading, among other things, to the mobilization of calcium ions and subsequent degranulation. According to the illustration, this Ca 7" mobilization is caused at a later stage of the Esse KI signal transduction pathway. As mentioned above and shown in Fig. 3, ionomycin directly 65 causes mobilization of Ca? and flow of Ca?, which leads to degranulation. Other ionophores causing degranulation in this way include A23187. The ability of ionophores, such as ionomycin, to bypass the early stages of the Ese CI and/or Esu CI signaling cascades can be used as a counting screen to identify active compounds of the present invention that specifically exert their activity to inhibit degranulation by blocking or inhibiting the early Ese CI or Esu signaling cascades CI, as discussed above. Compounds that specifically inhibit such early Ese KI or Esu KiI-mediated degranulation inhibit not only degranulation and the subsequent rapid release of histamine, tryptase, and other granule contents, but also proinflammatory activation pathways that cause the release of TME o, II/-4, I/-13 and lipid mediators, such as I! TC4. Thus, compounds that specifically inhibit such early EsCI and/or EsCI-mediated degranulation also block or inhibit acute atopic or Type I hypersensitivity reactions and the late response involving many inflammatory mediators.

Compounds according to the present invention that specifically inhibit early Ese KI and/or Psu Ki-mediated degranulation are those compounds that inhibit Ese KI and/or Esu KI-mediated degranulation (e.g. with an IC value of less than 20 μmol relative to the release of a granule-specific mediator or 75 components according to the results of measurement in IP migo quantitative analysis with the participation of cells stimulated

ISE or IDS-binding agent), but slightly inhibit ionophore-induced degranulation. In one embodiment, compounds are considered to slightly inhibit ionophore-induced degranulation if their IC 50 value of ionophore-induced degranulation is greater than 20 μmol as measured by the IP assay. It is clear that active compounds characterized by a higher value of |C0 of ionophore-induced degranulation, or those that do not inhibit ionophore-induced degranulation at all, are particularly effective. In another embodiment, compounds are considered to not significantly inhibit ionophore-induced degranulation if they demonstrate a greater than 10-fold difference in the magnitude of IC values for Ese CI and/or Ese CiI-mediated degranulation and ionophore-induced degranulation as determined by IP migo analysis. Assays that can be used to determine the C value of ionophore-induced degranulation include any of the previously described degranulation assays provided that the cells are stimulated or activated with a degranulation-inducing calcium ionophore such as ionomycin or A23187 (A.O. Zsiepiis, Zap Oiedo, CA), instead of anti-IDE antibodies or

IDE-specific allergen. Specific assays to assess the ability of a particular 2,4-pyrimidinediamine compound of the present invention to inhibit ionophore-induced degranulation are provided in the Examples section. co

Those skilled in the art will agree that compounds that exhibit a high degree of selectivity for Bso Tech!

KI-mediated degranulation, find a certain application, since such compounds selectively act on Es

KI cascade and do not affect other mechanisms of degranulation. Similarly, compounds that exhibit a high degree of selectivity in relation to Esu KiI-mediated degranulation find some use, since such compounds selectively act on the Esu Ki cascade and do not affect other mechanisms of degranulation. Compounds that exhibit a high degree of selectivity are generally 10 or more times selective in relation to Es

KI- or Psu KiI-mediated degranulation compared to ionophore-induced degranulation, such as ionomycin-induced degranulation.

Biochemical and other data confirm that the 2,4-pyrimidinediamine compounds presented in this paper are "strong inhibitors of Zuk-kinase activity." For example, in experiments with isolated Zuk kinase, all but two of the twenty-four tested 2,4-pyrimidinediamine compounds inhibited catalyzed . Phosphorylation of a peptide substrate with IC values in the submicromolar range by Buk-kinase. The remaining compounds inhibited phosphorylation in the micromolar range. In addition, all sixteen compounds tested in the mast cell IP assay inhibited the phosphorylation of Zuk kinase substrates (e.g., RI. C-dattai|, GAT) and proteins downstream of Zuk kinase (e.g., MK, pZ8, oo EgKkI/2 and RKV, when tested), but did not inhibit proteins in the reverse direction from Zuk-kinase in the cascade (for example, I up). The tested 2,4-pyrimidinediamine compounds did not inhibit the phosphorylation of I Uup substrates. Moreover, for the following compounds, a high correlation was observed between their ability to inhibit Buk-kinase activity in biochemical assays (IC50 in the range from 3 to 185O0nmol) and inhibition of EszKI-mediated degranulation in mast cells (IC50 in the range from 30 to 165O0nmol) : КУ50373, КО50368, К921302, К921302, with КО45371, К945370, к945369, кКО45365, КО21304, к921304, КО45144, К945140, к945071, КО40358, КО40353,

Ф КО40352, К940351, К940350, кКО40347, КО21303, кК921303, КО40338, К940323, к940290, Коо40277, КО40276,

КО40275, К940269, к940255, КО35393, КО35372, К935366, КОЗ5310, КО935309, кKOZ35307, КО35304, кKOоZ35302,

КОЗ35293, К935237, К935198, КОЗ35196, КОЗ35194, К935193, КОЗ5191, К935190, кКОЗ5138, КО27050, КО26968, вв К926956, 926931, КО26891, 926839, К926834, КО26816, 926813, К926791, К926782, 926780, 926757,

КО26753, К926745, к926715, кKO26508, КО26505, кК926502, КО26501, К926500, кKUо21218, КО21147, КО20410, (F) Кко09268, К921219, к908712, к908702. t The activity of the 2,4-pyrimidinediamine compounds proposed in this invention can also be confirmed by biochemical or cellular Zuk kinase activity assays. As shown in Fig. 2, in the ESKI signaling cascade in mast and/or basophil cells, Zuk kinase phosphorylates GAT and RI C-gamma, which leads, among other things, to degranulation. Any of these actions can be used to confirm the activity of the 2,4-pyrimidinediamine compounds of this invention. In one embodiment of the present invention, activity is confirmed by contacting isolated Zuk kinase or its active fragment with a 2,4-pyrimidinediamine compound in the presence of a Zuk kinase substrate (eg, a synthetic peptide or protein known to be phosphorylated with the help of Zuk in the signaling cascade) and assessment of the fact of phosphorylation of the substrate by Zuk kinase. Alternatively, the assay can be performed with cells that express 5uk kinase. Cells can express Zuk kinase endogenously, or they can be engineered to express recombinant Zuk kinase. Cells can also additionally express a Zuk kinase substrate. Cells suitable for use in such confirmatory assays, as well as appropriate methods for generating such cells, will be apparent to those skilled in the art. Specific examples of biochemical and cellular assays suitable for confirming the activity of 2,4-pyrimidinediamine compounds are provided in the Examples section.

In general, for compounds that inhibit Zuk kinase, the IC 50 value in relation to Zuk kinase activity, such as the ability of Zuk kinase to phosphorylate a synthetic or endogenous substrate, will typically be in the range of about 200 μmol or less in an IP or cellular assay. Those skilled in the art will agree that compounds characterized by low IC 50 values, such as in the range of 10 µmole, 10 µmole, 10 µmole, 1 µmole, 1 µmole, or even lower, are particularly useful.

Applications and Compositions

As previously described, the active compounds of the present invention inhibit the signaling cascades of Es receptors, especially those Es receptors that contain a gamma homodimer, for example the signaling cascades of Ece CI and/or Psu CI, which 7/5 lead, among other things, to the release and/or synthesis of chemical mediators from cells through degranulation or other processes. Also, as previously described, the active compounds are effective Zuk kinase inhibitors. Therefore, the active compounds of the present invention can be used in a variety of ip migo, ip mimo, and ex mimo contexts to regulate or inhibit Zuk kinase, signaling cascades in which Zuk kinase plays a role, signaling cascades

ES receptors, and biological reactions caused by such signaling cascades. For example, in one embodiment of the present invention, the compounds can be used to inhibit Zuk kinase, ip migo or ip mimo, in virtually any cell type that expresses Buk kinase. They can also be used to regulate signal transduction cascades in which Zuk kinase plays a role. Such Zuk-dependent signal transduction cascades include, but are not limited to, Es CI, Esu CI, Esu CI, VSK, and integrin signal transduction cascades. These compounds can also be used ip mygo or ip mimo for the regulation of, and in particular the inhibition of, cellular or biological responses due to such Zuk-dependent signal transduction cascades. Such cellular or biological responses include, but are not limited to, respiratory bursts, cell adhesion, cell degranulation, cell spreading, cell migration, cell aggregation, phagocytosis, cytokine synthesis and release, cell maturation, and Ca 7 flux.

Importantly, these compounds can be used to inhibit Zuk-kinase as a therapeutic approach (se) to the treatment or prevention of diseases mediated entirely or in part by Zuk-kinase activity.

Non-limiting examples of Zuk kinase-mediated diseases that can be treated or prevented with F using such compounds are provided in more detail below. -

In another embodiment of the invention, the active compounds can be used to regulate or inhibit the signaling cascades of Es receptors and/or Es CI- and/or Es CI-mediated degranulation as a therapeutic approach to the treatment or prevention of diseases characterized by, caused by, and/or caused by associated with c o) release or synthesis of chemical mediators, such as signaling cascades of Es receptors, or degranulation.

Such treatment can be prescribed to animals for veterinary purposes or to humans. Diseases characterized by, caused by, or associated with such mediator release, synthesis, or degranulation, and therefore amenable to treatment or prevention with the active compounds, include, but are not limited to, the following: atopy, atopic or anaphylactic hypersensitivity or allergic reactions, allergies - c (for example, allergic conjunctivitis, allergic rhinitis, atopic asthma, atopic dermatitis and food allergy), low level of scarring / for example, scleroderma, increased fibrosis, keloid formation, postoperative scars, pulmonary fibrosis, vasospasm , migraine, reperfusion injury and post-myocardial infarction), diseases associated with tissue destruction (eg, chronic obstructive pulmonary disease (COPD), cardiobronchitis and post-myocardial infarction), diseases associated with tissue inflammation co (eg, syndrome irritable bowel, spastic colon and inflammatory bowel disease), inflammation and scarring. o In addition to a number of diseases listed above, data from studies at the cellular level and data from studies - in animals indicate that the 2,4 pyrimidinediamine compounds according to the present invention can be used for the treatment or prevention of autoimmune diseases and/or various symptoms, etc. associated with such diseases. To autoimmune diseases that can be treated or prevented with

GI with the help of 2,4-pyrimidinediamine compounds generally refers to disorders associated with tissue damage caused by a humoral and/or cell-mediated response to immunogens or antigens of endogenous and/or exogenous origin. Such diseases are often called diseases associated with non-anaphylactic hypersensitivity reactions (type II, type I, and/or type IM hypersensitivity reactions).

As previously discussed, type I hypersensitivity reactions are generally due to the release of pharmacologically active substances, such as histamine, from mast and/or basophil cells as a result of contact with a specific exogenous antigen. As mentioned earlier, reactions of the type ! play a role in many diseases, including allergic asthma, allergic rhinitis, etc. 60 Type 0 hypersensitivity reactions (which are also called cytotoxic reactions, complement-dependent cytolysis reactions, or cell-stimulating hypersensitivity reactions) are due to the reaction of immunoglobulins with antigenic components of a cell or tissue, or with an antigen or hapten attached to a cell or tissue. Diseases associated with type I hypersensitivity reactions include, but are not limited to, autoimmune hemolytic anemia, hemolytic disease of the newborn, and Goodpasture syndrome.

Type P hypersensitivity reactions (which are also called hypersensitivity reactions due to toxic,

soluble or immune complexes) are caused by the deposition of soluble circulating antigen-immunoglobulin complexes in vessels or tissues and are accompanied by acute inflammatory reactions at the site of immune complex deposition. Non-limiting examples of diseases that develop according to type II reactions,

These include Arthus phenomenon, rheumatoid arthritis, serum sickness, systemic lupus erythematosus, some types of glomerulonephritis, multiple sclerosis, and bullous pemphigoid.

IM-type hypersensitivity reactions (which are often called cellular, cell-mediated, delayed, or tuberculin-type hypersensitivity reactions) are caused by synthesized T-lymphocytes as a result of contact with a certain antigen. Non-limiting examples of diseases that develop in type 7/0 MI reactions include contact dermatitis and allograft rejection.

Autoimmune diseases associated with any of the above non-anaphylactic hypersensitivity reactions can be treated or prevented with the 2,4-pyrimidinediamine compounds of the present invention.

In particular, these agents can be used for the treatment or prevention of autoimmune diseases, which are often attributed to autoimmune disorders of a single organ or a single cell type and which include, but are not limited to, /5 autoimmune thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis, pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture syndrome, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Bazed disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis, and membranous glomerulopathy, as well as autoimmune diseases that are often referred to as systemic autoimmune disorders and include but are not limited to are limited to the following: systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, periarteritis nodosa, multiple sclerosis, bullous pemphigoid.

Those skilled in the art will agree that reducing the acute symptoms of most of the above-mentioned autoimmune diseases provides a significant therapeutic benefit even when the underlying disease is not amenable to improvement. Many of these symptoms, as well as the stages of major diseases, are caused by the activation of the Esu K signaling cascade in monocyte cells. Since the 2,4-pyrimidinediamine compounds of this invention are strong inhibitors of such Esu K signals in monocyte and other cells, these agents i) are used in the treatment and/or prevention of a number of acute symptoms accompanying the above-mentioned autoimmune diseases.

For example, rheumatoid arthritis (RA) causes swelling, pain, loss of mobility and sensitivity of the affected joints throughout the body. CA is characterized by chronic inflammation of the synovial membrane, which is densely filled with lymphocytes. The synovial membrane, which is typically a single cell layer, becomes densely packed with B cells and takes on a form similar to lymphoid tissue, including dendritic cells, T-, B-, and MK cells, macrophages, and clusters of plasma cells. This process, as well as an excessive number of immunopathological mechanisms, including the formation of antigen-immunoglobulin complexes, leads to the destruction of the integrity of the joint, which leads to deformation, irreversible loss of function and/or erosion of the bone of the joint or near the joint. co

The methods of the present invention can be used to treat and reduce one, more, or all of the symptoms

CA. Therefore, in the context of KA, these methods are considered to provide a therapeutic outcome (more generally described below) when a reduction or improvement of the symptoms inherent to KA is achieved, regardless of the outcome of the concomitant treatment of the underlying disease (KA) and/or a reduction in the amount of circulating " 470 rheumatoid factor (RF). 2 s In another specific example, systemic lupus erythematosus (5E) is typically characterized by fever, joint pain (arthralgia), arthritis, and serositis (pleurisy or pericarditis). In the context of IE, the methods of the present invention are considered to provide a therapeutic outcome when a reduction or improvement of the symptoms inherent in IE is achieved, regardless of the outcome of the accompanying treatment of the underlying disease. As another specific example, multiple sclerosis (MS) causes sufferers have visual disturbances; development of double vision; impaired motor function that affects the ability to walk and use hands; and causes urinary and fecal incontinence; spasticity; and limited sensory (to touch, pain, sensitivity to - temperature). In the context of M5, the methods of this invention are considered to provide a therapeutic result when a reduction or improvement of one or more symptoms inherent in M5 is achieved, regardless of the result of the accompanying treatment of the underlying disease. b When used for the treatment or prevention of such diseases, the active compounds can be used separately, in the mixtures of one or more active compounds or in solution or in combination with other substances used to treat such diseases and/or symptoms associated with such diseases. These active compounds are also used in solution or in combination with substances that are used to treat other disorders or disorders, such as steroids, membrane stabilizers, (F. BI O-inhibitors, leukotriene synthesis and receptor inhibitors, IDE isotype transfer inhibitors or ICE synthesis inhibitors , co isotype transition of DS or synthesis of Ids, Dr agonists, tryptase inhibitors, aspirin, COX inhibitors, methotrexate, anti-TME drugs, retuxin, PO4 inhibitors, p38 inhibitors, POE4 inhibitors, and antihistamines, etc. 60 active compounds can be used reg ze (on its own) in the form of prodrugs or medicinal preparations of pharmaceutical compositions that contain an active compound or prodrugs.

Pharmaceutical compositions containing active compounds according to the present invention (or prodrugs thereof) can be prepared using conventional mixing, dissolving, granulating, dragee-forming demulsification, emulsifying, encapsulating, entrapping or lyophilizing processes. These compositions can be prepared in a conventional manner, using one or more physiologically acceptable carriers, solvents, fillers or additional substances that facilitate the processing of active compounds into preparations for use in pharmaceutical purposes.

The active compound or prodrug can be prepared in the form of pharmaceutical compositions reg ze, or in the form of a hydrate, solvate, M -oxide or a pharmaceutically acceptable salt, as described above. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but it is possible to form salts that are less soluble than the corresponding free acids and bases.

The pharmaceutical compositions of the present invention may take a form suitable for virtually any route of administration, including, for example, topical, ocular, internal, transbuccal, systemic, nasal, injectable, transdermal, rectal, vaginal, etc., or a form , convenient for use by inhalation or inhalation.

For topical application, the active compound(s) or prodrugs may be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art.

A systemic method includes the use of compounds that are intended for administration by injection, for example, subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those intended for transdermal, transmucosal, oral, or pulmonary application.

Medicinal products for injection include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily carriers. The compositions may also contain forming agents, such as suspending, stabilizing and/or dispersing agents. Injections can be prepared in the form of individual doses, for example, in ampoules or multidose containers, and may contain added preservatives.

Alternatively, the injectable drug may be prepared as a powder to which a suitable excipient (solvent) is added for reconstitution prior to use, including but not limited to sterile, pyrogen-free water, buffer, glucose solution, etc. For this purpose, the active compound(s) may be dried by any known means, such as lyophilization, and reconstituted prior to use.

For use through the mucous membrane, wetting reagents are used in medicines that correspond to the existing barrier. Such substances are known in the art.

For oral administration, pharmaceutical compositions may take the form of, for example, pastilles, tablets, or capsules prepared by conventional methods using pharmaceutically acceptable carriers, such as binders (eg, pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (for example, lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example, magnesium stearate, talc or quartz); "- disintegrating substances (for example, potato starch or sodium starch glycolate); or humectants (such as sodium lauryl sulfate). Tablets can be coated using well-known methods. EM with such substances as, for example, sugar, films or enteric coating. Compounds that are particularly suitable for oral administration include compounds K940350, K935372, K935193, K9U27050 and K9UZ35391.

Liquid medicaments for oral administration may be in the form of, for example, elixirs, solutions, syrups or suspensions, or may be in the form of a dry product which is dissolved in water or other suitable excipient before administration. Such liquid medicines can be prepared by conventional means using "Pharmaceutically acceptable additives, such as suspending agents (for example, sorbitol syrup, cellulose derivatives - c or hydrogenated food fats); emulsifying agents (for example, lecithin or acacia); anhydrous fillers (for example, almond oils, oil esters, ethyl alcohol, cremofort or fractionated vegetable oils); and preservatives (eg, methyl or propyl-p-hydroxybenzoates or sorbic acid). If necessary, preparations may also contain buffer salt, preservatives, flavorings, dyes, etc

Sweeteners.

Go! As is well known, drugs for oral administration can be properly formulated to provide controlled release of the active compound or prodrugs. For transbuccal use, the compositions can be in the form of tablets or lozenges, and prepared in the traditional way.

For rectal and vaginal use, the active compound(s) may be formulated as solutions (for retention enemas), suppositories, or ointments containing a traditional suppository base such as cocoa butter

FO or other glycerides.

For nasal administration or administration by inhalation or insufflation, the active compound(s) or prodrugs may conveniently be delivered as aerosols for nebulization from pressurized canisters or a nebulizer using a suitable agent, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbon, carbon dioxide, or other suitable gas. In the case of application (F; aerosol under pressure, the dosage can be determined by means of a valve to deliver a metered quantity. t Capsules and canisters for use in an inhaler or insufflation device (for example, capsules and canisters consisting of gelatin) can be prepared as , to contain a powder mixture of the compound and a suitable powder base, such as lactose or starch.

A specific example of an aqueous suspension formulation suitable for nasal administration using commercially available intranasal aerosol devices includes the following ingredients: active compound or prodrug (0.5-2Omg/ml); benzalkonium chloride (0.1-0.2mg/ml); polysorbate 80 (TMUEEMEA 80; 0.5-5mg/ml); sodium carboxymethyl cellulose or microcrystalline cellulose (1-15 mg/ml); phenylethanol (1-4mg/ml); and 65 dextrose (20-5Omg/ml). The pH of the final suspension can be adjusted from about pH 5 to pH 7 with a typical pH of 5.5.

In another specific example, an aqueous suspension suitable for the use of the compound. In the form of inhalation, and in particular for the use of the compound K9U21218, contains 1-20mg/ml of the compound or prodrug, 0.1-1956 (by volume) of polysorbate 80 (TU /EEMO 80), 5 BOMM citrate and/or 0.995 sodium chloride.

For ophthalmic use, the active compound(s) or prodrug may be formulated in the form of a solution, emulsion, suspension, etc., suitable for ophthalmic use. Various excipients suitable for use with compounds used for ophthalmic applications are well known in the literature. Some specific examples are described in (US patents Mob261547; Mob197934; MobO56950; Mo5800807; Mo5776445; Mo5698219; Mo5521222;

Mo5403841; Mo5077033; Mo4882150; and Mo47388511. 70 For long-term action, the active compound(s) or prodrugs can be formulated as a slow-absorbing formulation administered by implant or intramuscular injection. The active ingredient can be prepared using suitable polymeric or hydrophobic materials (eg, emulsion in suitable oils) or ion-exchange resins, or in the form of derivatives with poor solubility, for example, a poorly soluble salt. Alternatively, transdermal delivery systems, made in the form of an adhesive disc or patch, can be used that slowly release the active compound or compounds for subcutaneous absorption. For this purpose, substances can be used that contribute to the penetration of the active compound(s) during subcutaneous use. Examples of suitable patches for transdermal use are described in (US patents Mo5407713; Mo5352456; Mo5332213; Mo5336168; Mo5290561; Mo5254346; Mo5164189; Mo5163899;

Mo5088977; Mo5087240; Mo5008110; and Mo4921475).

Alternatively, other drug delivery systems may be involved. Liposomes and emulsions are well-known examples of carriers that can be used to deliver active compound(s) or prodrugs. Certain organic solvents such as dimethylsulfoxide (OM5O) can also be used, but this usually results in greater toxicity.

Pharmaceutical compositions can, if necessary, be presented in the form of a package or a dispensing device, which can contain one or more doses of the active compound(s). This packaging may include, for example, metal or plastic foil, such as a blister pack. The package or dispensing device may contain (8) instructions for use.

Effective doses

The active compound(s) or prodrugs of the present invention, or compositions thereof, will generally be used in an amount effective to achieve a desired result, such as in an amount effective to treat or prevent a particular disease. The compound(s) can be used therapeutically to achieve a therapeutic result or prophylactically to achieve a prophylactic result. Therapeutic outcome refers to the eradication or reduction of the underlying disorder that is the object of treatment and/or the eradication or improvement of one or more symptoms associated with

З5 is a major disorder to the extent that the patient feels an improvement in well-being or health, even though he continues to suffer from the underlying disorder. For example, administration of a compound to an allergic patient provides a therapeutic effect not only when the underlying allergic reaction is eradicated or attenuated, but also when the patient experiences a reduction in the severity or duration of allergy-related symptoms as a result of exposure to the allergen. In another example, the therapeutic outcome in the case of asthma includes improvement in breathing after an asthma attack or reduction in the frequency or severity of asthmatic episodes. Therapeutic - c result also includes stopping or slowing down the progress of the disease, regardless of the presence of improvement. For prophylactic use, the compound can be used by a patient at risk of developing one of the previously described diseases. For example, if it is not known whether the patient has an allergy to certain drugs, the compound can be used

Apply before taking medications to avoid or reduce allergic reactions to these medications. оо Alternatively, prophylactic use can be carried out in order to avoid the manifestation in the patient of symptoms associated with the underlying disorder. For example, the compound may be administered to an allergic patient prior to expected exposure to the allergen. The compounds can also be used prophylactically by healthy individuals repeatedly exposed to agents associated with the aforementioned diseases to prevent the onset of disorders. For example, the compound may be administered to a healthy individual (Ce) who is repeatedly exposed to an allergen known to cause allergies, such as latex,

Pho in order to prevent the development of allergies. Alternatively, the compound may be administered by a person suffering from asthma prior to engaging in an activity that causes asthma attacks to reduce the severity or completely avoid the occurrence of asthmatic episodes.

The amount of compound administered will depend on a variety of factors, including, for example, the specific indications of the disease, the route of administration, whether the treatment is prophylactic or therapeutic, the severity

HF) course of the disease, age and weight of the patient, bioavailability of a certain active compound, etc. Effective dose

F is easily determined by specialists.

Effective doses can initially be determined using the results of an ip migo analysis. For example, a primary dose for an animal can be formulated so that the circulating blood or serum concentration of the active compound equals or exceeds the IC50 value for a particular compound according to the results of an ip migo assay, such as ip migo CHMS or BMMS, and other ip migo assays , described in the "Examples" section. The exact dose required to achieve such a concentration in the circulating blood or serum, taking into account the bioavailability of a particular compound, is easily determined by a person skilled in the art. For further 65 advice, the reader can turn to IRipo! 5 UUoodrigu, "Sepega!| Rgipsiriev," ip: boodtap apa Sitap from Tpe

Rpagtaseciisai Vaziz oi TPegareciisv, Sparieg 1, pp. 1-46, Iaievi eijop, Radatopop Rgevz5, and references, -BO0-

given in this book.

Primary doses can also be calculated on the basis of ip mimo data, for example based on experimental animal models. Experimental animal models used to test the efficacy of compounds for the treatment or prevention of the various diseases described above are well known in the literature. Appropriate experimental animal models for the study of hypersensitivity reactions or allergic reactions are described in the following sources: Bovzieg, 1995, APegdu 50 (215!yrriI): 6-9, aizsivzviop 34-38 and Titavz ei ai., 2001, 9). AiPegdu Siip. And so on. 107 (6): 1025-1033). Appropriate animal models for the study of allergic rhinitis are described in (ZgeiIepui ei ai.,, 2000, AggpeiitShSchenogespipud 50(11): 1037-42; 7/0 Kazhadispi ei a. 1994, Sip. Ehr. APegou 24 (3): 238-244 apa Zyditoyu eyi ai., 2000, Ittyporpagtasoiodo 48(1): 1-7). Appropriate animal models of allergic conjunctivitis are described in ISagttegaz eii ai., 1993, Vg. ..

Orpipa|toi. 77(8): 509-514; Zaida ei ai, 1992, OrpiNaItis Kev. 24(1): 45-50; and Kypepy eyi ai., 2001, Ipmevi.

Orpia|toi. Said All together. 42(11): 2483-2489). Appropriate animal models for the study of systemic mastocytosis are described by O'Keeee et al. 1987, 9. Mei. Ipiegpa Maya 1 (2): 75-80 and Veap-Kpydzep et al., 1989, Mei. 7/5 Raipoi. 26 (1): 90-92). Appropriate animal models of hyper DE syndrome are described in Siap et al., 1990, Siip

And so on. Ittiporaiyoi. 56(1): 46-53). Appropriate animal models of B-cell lymphoma are described in (Notsodp ei ai., 1998, Rgos. Man. Asad. Zsi. OBA 95: 13853-13858 and NakKit ei aiYi., 1996, 9. Ittypoi. 157(12): 5503- 5511).

Appropriate animal models of atopic disorders, such as atopic dermatitis, atopic eczema, and atopic asthma, are described in (Spap ei AI, 2001, y. Ipmevi. Yueptaiyoi. 117 (4): 977-983 and that ei yi.,, 1999, Ipi Agsy . 2o AyMyegdu Ittipoi. 120 (Zirri 1): 70-75). In general, practitioners can easily apply this information to determine a dose that is suitable for human use. Additional relevant animal models are described in the Examples section.

Dose sizes typically range from about 0.0001 or 0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but may be higher or lower depending on, among other factors, the activity of the compound, its bioavailability, method of application and the various factors described above. The dose size and interval can be adjusted individually to ensure sufficient plasma levels of the compound to (8) maintain a therapeutic or prophylactic effect. For example, the compounds may be administered once a week, several times a week (eg, every other day), once a day, or many times a day, depending on, among other things, the route of administration, the symptoms of the disease, and the judgment of the prescribing physician. medicine. In cases of local application or selective administration, such as external application, the effective local concentration of the active compound(s) may not be related to the plasma concentration. b"

Specialists will be able to optimize effective local doses with the help of necessary experiments. "-

It is always desirable that the compound(s) provide a therapeutic or prophylactic effect without causing significant toxicity. The toxicity of a compound can be determined using standard EM pharmaceutical procedures. The ratio between the toxic and therapeutic (or prophylactic) effect of a given dose represents the therapeutic index. Preference is given to compounds with high therapeutic indices.

In addition to the description of the invention, the following examples are given below, illustrating its operation, but not limiting its application. 7. Examples « 7.1. Synthesis of starting materials and intermediate compounds useful for the synthesis of compounds - c 2,4-pyrimidinediamine according to schemes (1)-(M)

A significant amount of starting materials and M4-monosubstituted-2-pyrimidinamines, as well as from M2-monosubstituted-4-pyrimidinediamines (aromatic nucleophilic substitution reaction products (AMS)), which can be used for the synthesis of the 2,4-pyrimidinediamine compounds of this invention, has been synthesized according to schemes (I)-(C) as described below. The conditions suitable for the synthesis of toipo-5MAK products are demonstrated by the example of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine (K926087). ko - (Se) (42)

F) ko 60 b5

Section Name of compound and number Method of preparation Reference 7.4 Synthesis of starting materials and various starting materials and M4-monosubstituted-2-pyrimidinamines, as well as intermediate compounds useful for M2-monosubstituted-4-pyrimidinediamines (reaction products of the aromatic synthesis of compounds of 2,4-nucleophilic mixtures (5MAK)Y, which can be used for the synthesis of pyrimidinediamine according to the schemes (I)- | 2,4-pyrimidinediamine compounds representing the present invention, were synthesized (U) according to the schemes (1)-(U), as given below. The conditions suitable for the synthesis of mono-5CHAK products are demonstrated by the example of 2-chloro-M4-(3,4- ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine (K926087). 0.65 g (5 mmol) of 5-fluorouracil and then 1.53 g (10 mmol) of phosphorus oxychloride (RUSSIA) are added to a dry reactor with a stirrer and an irrigation condenser.

The resulting mixture is heated and kept at a temperature of 110 oC for 8 hours in a nitrogen atmosphere. Next, the reaction mixture is cooled to room temperature, phosphorus pentachloryl (PCI5) (3.12 g, 15 mmol) is added and heated to 110 oC for 12 hours. After cooling to room temperature, the mixture is poured into ice water, saturated with sodium chloride and left for | hour at room temperature to complete the decomposition of ROSIZ and RS15. The 2,4-dichloro-5-fluoropyrimidine solid was collected by rapid filtration, dried with blotting paper, and stored at low temperature. 1H NMR (nuclear magnetic resonance) (SOSIZ): 3,847 (5, 1NU; ISR NMR (SOSIZ3): 1: 155.42, 151.87, 147.43 and 147.13; 19Z NMR (SOSIZ - 38149, 7.12 2,4-dichloro-5-nitropyrimidine (Aldrich) A suspension of 5-nitrouracil (10 g, 63 mmol) is boiled in ROSIZ (100 ml) and

Ob, 930-0) is condensed for 5 hours in the presence of M,M-dimethylaniline (10 ml), then cooled to room temperature and, with thorough stirring, poured onto crushed ice. The formed water layer is removed using ethyl acetate. The combined organic layers were dried over Me5O4 and the solvent was removed under reduced pressure. The residue is purified by chromatography on silica gel (hexane/ethyl acetate; 1/1) by volume) to give the desired 2,4-dichloro-5-nitropyrimidine. LC/MS (liquid chromatography/mass spectrometry): retention time: 23.26 minutes; purity: 955; IN NMR (SOSIZU: 89.16 (1H, 5). 7.1.3 2,4-dichloro-5-cyanopyrimidine Analogously to the preparation of 2,4-dichloro-5-nitropyrimidine, 2,4-dichloro-5-semicyanopyrimidine dry remidine is obtained as a result of the reaction of 5-cygnouracil, ROSIZ and MM-Ge) dimethylaniline. LC/MS: retention time: 13.75 minutes; purity: 9595, 7.14 2,4-dichloro-5-trifluoromethylpyrimidine Analogously to the preparation of 2,4-dichloro-5-nitropyrimidine, 2,4-dichloro-5-cyanopyrimidine is obtained as a result of the reaction of 5-pnanuracil, ROSIZ and MM-dimethylaniline . INYAMR (СО3ОЮ); 5 9.07; LC/MS: retention time: 16.98 minutes (rapid method); purity: 7095. (Te 731.8 2-chloro-M4A-(3,4-ethylenedioxyphenyl)-5- Reactor with a magnetic stirrer and a rubber membrane (to prevent fluoro-4-pyrimidinamine (K926087) 2,4-dichloro-5 -fluoropyrimidine) and M2 delivery medium is filled with (e") 3,α-styrenedioxyaniline (34 g, 225 mmol), MeOH (100 ml), H2O (300 ml) and 2,4-dichloro-5-fluoropyrimidine (25 g , 150 mmol). The reaction mixture is stirred at room temperature for an hour, then dissolved in water (1.5 L), acidified with 2M HCl (200 ml) and dispersed using ultrasound. The resulting solid is filtered, washed with water and dried to give 33 g (7895) of the final product, 2-chloro-44-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimylinamine (K926087). IN NMR (SOSIS): 0 so 802 IN, 4 ,21 3 Hz), 7.25 (0, 1H, 225 1.2 P), 6.98 (44, 1H, 1- 2.4 and 8.1 Hz), 6.85 (4, 1H, 1 -57 Hz), 4.27 century, 4H)U; 192 YM (SOSIZ): -44570; RH/MS; duration of detention: 26.70 minutes; purity: 10029; MS (mass/charge): 283 (MI g). 716 2-chloro-M443 4 ethylenedioxyphenyl)-5" Similar to the preparation of 2-chloro-144-(3,4-ethylenedioxyphenyl)-5-fluoro-4-nitro-4-pyrimidinamine (2940094) pyrimidineamine, 2-chloro-M4- 3,4-ethylenedioxyphenyl)-5-nitro-4-pyrimidinediamicin is obtained as a result of the reaction of 2,4-dichloro-5-nitropyrimidine and 3,4-ethylenedioxyaniline. РХ/МС : duration of retention; 28.79 minutes; purity: 9095;

MS (mass/charge): 308 (Mk); IN NMR (SOSIS): 110.07 (1Н, 5), 9.15 (1Н, 5), 7.02- - с 6.88 (ЗН, m), 4.29 (4Н, 5)р 717 2-chloro -M4-(3-hydroxyphenyl)-5-nitro-4- Similar to the preparation of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-in! c» pyrimidineamine (К9У40097) pyrimidineamine, 2-chloro-M4-(3-hydroxyphenyl)-5-nitro-4-nyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-nitropyrimidine and 3-hydroxyanilic, LC/MS: retention time: 24.21 minutes; purity: 9355; MC (mass/charge): 267 (MN); IN NMR (SOSIZ): (110.20 (1H, z), 9.19 (16, sec, 7.32 (IN, 61: 2.2 tsu, 728 (IN, 4, 25 7.8 Go), 7.11 ( IN, ad, 1- 7.8 and 5.8 Go), 7.76 (IN, yes, 3- so 8.4 and 2.4 Hz), 5.20 (IN, 5). 71.8 2 -chloro-M4-(3-hydroxyphenyl)- 3-fluoro-4- Analogously to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4- from pyrimylinamine (926111) pyrimidineamine, 2-chloro- m4-(3-hydroxyphenyl)-5-fluoro-4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-

Shk of hydroxyaniline. IN NMR (SPZOI): GI 8.06 (5d, NO, 7.26 (bd, 1NU, 7.20-7.00 (m. -y (Se) 42) ko 60 b5

2H), 6574, IN, I- 7.5 Hz; 19E NMR (SOZOBU: 44374: LC/MS: retention time: 22.02; purity: 0095, MS (mass/charge): 240 (MN. 7415 2-chloro-M4-(3,4-dimethoxyphenyl)-5- fluoro- | Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4- 4a-pyrimidinediamine (K926073) pyrimidineamine, 2-chloro-M4-(3,4-dimethoxyphenyl)-5-fluoro -d-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoronyrimidine and 3,4- dimethoxyaniline.IN NMR (SOSIS): Gi 8.02 (0.1H, I 2.7Ho), 7.386, 1H, 3 WHAT

Hz), 7.054, IN, 32 2.4 and 9.0 Gk), 6.89 (5, 1), 6.884, 1H, 2-9 Gy), 3.91 (in, ZNU, 3.89 (5, ZN ); 192 NMR (SOSIZ): -44593; LC/MS: retention time: 24.95 minutes; purity: 9895; MS (mass/charge): 285 (MNK) tllo 2-chloro-M4-(4-ethoxyphenyl)-5 -fluoro-4- Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine (5926066) pyrimidineamine, 2-chloro-M4-(y-ethoxyphenyl)-5-fluoro-4 -pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-ethoxyniline. IN NMR (SOSIS): 08.01 (0, 1H, 22 Hz), 7.49 (Ly, 2H, 3-8 .7 Hz), 6.92 (64, 2H, 32 9.6 Hz), 4.03 (4, 2H, 1 7.2 Hz), 1.42 ( ЗН, 12 7.9 Hz); SE NMR (SOSISU: -44627; LC/MS: retention time: 29.50 minutes; purity: 9995, MS (mass/charge): 268 (MNN. 741 2-chloro-m4-(4-chlorophenyl)-5-fluoro -4- Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimilinamine (5926207) pyrimidineamine, 2-chloro-M4-(4-chlorophenyl)-5-fluoro-4- pyrimylinliamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-chloro raniline IN NMR (SOSIS): d) 8.1 (b5, 1H), 8.60 (Bad, 2H), 8.36 (hyd, 2NU, 6.90 (b5, IN); 19E NMR (SRSIZ): - 44407; LC/MS: retention time: 31.63 minutes; purity: 8595; MS (mass/l charge): 258 (MN). 74112 2-chloro-5-fluoro-M443-hydroxy-4- Analogous to the preparation of 2-chloro -M4-4(3,4-etipenedioxyphenyl)-5-fluoro-4-methoxycarbonylmethyleneoxyphenyl)-4-pyrimidinamine, 2-chloro-3-fluoro-M4-(3-hydroxy-4-pyrimidinamine (5926393) methoxycarbonylmethyleneoxyphenyl)-4 -pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methoxycarbonylmethyleneoxyaniline, 1 NMR (SBZOB): o 8.03 (a, 1H, 1 3.6 tsu, 7.35(46 , 1H, 1-2 2.45 Hu), 7.12 (a, 18, 4-24 and 8.7 Hz), 6.87 (6.18, 7 8.1 Hyd), 4.86 (in . 295), 3.81 (5, ЗН). 741.13 Ma4-(4-tert- Analogously to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-butoxycarbonylmethyleneoxyphenyl)-2-pyrimidinamine, 2-chloro-5-fluoro-M4-(3-hydroxy-4-chloro-5-fluoro-4-pyrimidinamine methoxycarbonylmethyleneoxyphenyl)-4-pyrimidinamine is obtained as a result of (926573) p reactions of 2,4-dichloro-5-fluoropyrimidic and tert-butyl-4-aminophenoxyacetate. 16

YAMRISOSIS): 0 8.02 (0, 1H, 3-- 2.7 Gy), 7.51 (49, 18, 3- 8.7 Hz), 6.93 (4, 1H, 3- 8.7 Ha

Go), 4.52 (5, 28), 1.49 (5, UNU RH/MS: retention time: 29.50 minutes: purity: 9795; MS (mass/charge: 354 (MNK). o 74414 2- chloro-5-fluoro-M4-(indol»5-yl)-4- Analogous to the preparation of 2-chloro-M443,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine (2926581) pyrimylinamine, 2-chloro-5-fluoro -M4-(indole-5-1l)-4-pyrimidinamine is restrained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 5-aminoindole. IN NMR (SOSIZ - SOZOBU: 0 9.45 (05, 1Н), 8 ... retention time: 23.85 minutes, purity: (se) 10095, MS (w/w): 263 (MNE).

Lava 2-chloro-5-fluoro-M4-(4-methoxymethyl- Analogously to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4- (22) coumarin-7-yl)-4- pyrimidineamine pyrimidineamine, 2-chloro-5-fluoro-M4-(4-methoxymethyl-coumarin-7-yl)-4- (К926518) pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and h- 4 methoxymethyl- 7-aminocoumarin. IN NMR(COSO): o 8.05 (4, 1), 7.90 (5.18), 7.720 (00, IN, 3- 2.4 and 8.7 Hz), 7.53 (d, 1Н , ze 8.7 Hz), 6.42 (5, 1Н), 4.61 (з, 2Н), 3.29 сх (5, ЗН); LC/MS: retention time: 26.38 minutes; purity: 879; MS (Masz/Zaryal): 336 (MN). 3o -- (ge) 741416 2-chloro-M4-(2,5-dimethyl-4- Analogous to the preparation of 2-chloro-Ma4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-hydroxyphenyl)-5-fluoro -4-pyrimidinamine | pyrimidine, 2-chloro-HM4-(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidinamine (K926619) is obtained as a result of the reaction of 2,4-dichloro-5-fluorothymidine and 2,5-limethyl- 4- hydroxyaniline, LC/MS: retention time: 23.31 minutes; purity: 9655; MC (mass/charge): 268 (MN). « 74147 2-chloro-M4-(5-chlorolyrid-2-yl)-5-fluoro-4- | Similarly to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenia)-5-fluoro-4-pyrimidinamine (K926061) pyrimidineamine, 2-chloro-M4-(5-chloropyriad-2-yl)-5-fluoro-4- pyrimidineamine s-b is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 5-chloro»2-s aminopyridine, PN NMR (SOSIZ): С) 8.40 (90, 1Н,, 7-5 8.7 Hz), 85.28 (y, IN, 15 8 Gnu 8.17 (4, 1H, 1-1 and 9 Gy); LC/MS: retention time: 28.58 minutes; purity: h » 10095; MS ( mass/charge): 259 (MH), " 74148 2-chloro-5-fluoro-M4-(5-methylpyrid-2-yl)) similar to the preparation of 2-chloro-M4-4(3,4-styrenedioxyphenia) -5-fluoro-4- 4-pyrimidinamine (К926062) pyrimidineamine, 2-chloro-5-fluoro-M4-(5-methylitride-2-1l)-5-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro - 5-fluoropyrimidine and 5-chloro-2-aminopyridine. 1H NMR (SOSIS): 0 9.20 (5, 1H), 8.51 (5, 1H)), 7.63 (9, 1H, 55.7 o gy), 7.458, 1H, 5- 1.8 and 9.3 Hz), 2.43 (5, ZN); LC/MS: retention time: 21.29 minutes; purity: 9795, MS (mass/zarkd ): 239 (MNK). preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-fluoro-4-pyrimidinamine, Ч4-1641,4-benzoxazinyl)|)-M2-chloro-5-fluoro-4-pyrimidinamine -y (Се) 42) ko 60 b5 are obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and b-amino-1,4-benzoxazine (in methanol or a solution of methanol in water). EN NMR (0M502-46): yZ 8.2 (a, 1НУ), 6.8 (t, 1Н), 6.75 (t, 1Н), 6.60 (t, 1Н0), 4.05 (t, 2Н), 3, 2 (t, 2H);

РЖЖ/МС: retention time: 20.8 minutes; purity: 95 95; MS (mass/charge): 295 (Mn. 7.1.20 M2-chloro-M4-(2,3-digylrobenzofuran-5-) Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4 - yl)-5-fluoro-4-pyrimidinamine pyrimidineamine, M2-chloro-M4-(2,3-dihydrobenzofuran-5-1l)-5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5- of fluoropyrimidine and 5-amino-2,3-digylrobenzofuran. IN NMR (PM5O-ybu and 8.092, 1), 8.00 (t, 1H), 7.42 (t, 2H), 7.05 (t, IN) , 4.53 (t, 2), 4.25 (5, 2H)), 3.15 (t, 2H); RZHU/MS: duration of detention: 20.35 minutes; purity: 90,996; MS (mass/charge): 266 (MIN-K). 74121 2-chloro-M44(2-carboxy-4-chlorophenyl)-5- Similar to the preparation of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-fluoro-4-pyrimidinamine (К940050) pyrimidineamine, 2-chloro-M4-(2-carboxy-4-chlorophenyl)-5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimiline and 2-carboxy-4-chloroaniline. LC/MS: retention time: 20.83 minutes; purity: 9895; YIN YAM? (SOSIZU; 8.64 (IN, a, 7- 4.8 Gou 8.24 (IN, 0, 1-2.7 Gy), 7.76 (1 H, da, ze 8.7 and 207

Go), 7.70 (NN, yes, 1 8.7 and 1: 0.9 Sy). 7.1.22 1h-(2-chloro-3-fluoro-4-pyrimidinyl). Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-methyl ether I-tyrosine (K940108) pyrimidineamine, M-(2-chloro-5-fluoro-4-pyrimidinyl)-methyl ether And -tyrosine is obtained as a result of the reaction of 7,4-dichloro-5-fluoropyrimidine and methyl ether

I-tyrosine. LC/MS: retention time: 23.32 minutes; purity: 8395; MS (mass/weight): 325 (MA); IN NMR (SOSIS): (17.90 (IN, 4, 3- 2.7 Gy), 6.95 (2Н, 4, 3- 8.7 Gy), 6.752Н, 4, 1- 8.7 Gy ), 5.95 (1H, 5), 5.72 (1H, 4, I 7.5 Gy), 5.05 (IN, db Te 7.5 and 5.3 GI), 3.77 (ZN, 5), 3.16 (2A, t). 7.1.23 2-chloro-MA-13-(5-cyano-2-methyl-4- Analogous to the preparation of 2-chloro-m4-(3 4-ethylenedioxyphenyl)-5-fluoro-4-thiomethyl-b-pyrimidinyl)phenyl |-5-fluoro- | pyrimidinamine, 2-chloro-M4-13-(5-piano-2-methyl-4-thiomethyl-b-pyrimidinyl)phenyl|- 4-pyrimidinamine (K9401413 5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4- dichloro-5-fluoropyrimidine and 3-(5-cyano-2-methyl-4-thiomethyl-b-pyrimidinyl)aniline. LC/MS: retention time: 18.23 minutes; purity: 8495; MS (mass/charge)u : 386 (M); |N

NMR (SOSIZ DC VLO(IN, 6 AND OGO) VL 1, b, 1-2 3.1 Ha), 7.98 (1Н, aa, 12 81 and 152.4 Hz), 7.82 (1Н, Iad, 727 .8 and 1.8 Gy), 7.57 (1H, 6.22: 7.8 Hz), 71 (IN, 5), 2.79

IZN, 5), 2.69 (ZN, 5). and Dimethyl sulfoxide se 7 o 74ALA M4-14-(M-benzylpiperazinephenyl-2- Analogous to the preparation of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-chloro-5-fluoro-4-pyrimidinamine pyrimidinamine, M4-14-(M-benzylpiperazine)phenyl)-2-chloro-5-fluoro-4-pyrimidinamine (8945154) is obtained as a result of the reaction of 2,4-dichloro-3-fluoropyrimidine and 2,4-dichloro-5-fluoropyrimidine . 1 NMR (SOSIS): 5 2.81 (t, 4 NI), 3.37 (to, 6 NU, 6.85 (t, X H), 6.93 (4, 7- 9.0 Gy, 2 H) , 7.40 (t, 5 H), 7.50 (d, 1- 9.3 Gy,, 2 H), 8.02 (4, 1- 2.7 Ha, 1

NO); LC/MS: retention time: 20.56 minutes, purity: 97.7590; MS (se) (mass/charge): 398.00 (MNE. 7.125 2-khpor-MA-(4-cyanomethyleneoxyphenyl)-5- | Similar to the preparation of M2,IM4-bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2 ,4-(22 fluoro-4-pyrimidinaminium (2945069) pyrimidinediamine, 2-chloro-M44(4-cyanomethyleneoxyphenyl)-5-fluoro-4-pyrimidinamine (110 mg, 6695) is obtained as a result of the reaction of M4-(4- or aminocarbonylmethyleneoxyphenyl )-2-chloro-5-fluoro-4-pyrimidinamine (178 me, 0.6 mmol), trifluoroacetic anhydride (0.17 mL, 1.2 mmol) and pyridine (0.15 mL, Ha 1.84 mmol) .IN NMR (acetone-db): δ 5.22 (5.2 H), 7.24 (a, 1-:9.3 Hz, 2 NU, 7.62 (y, 129.0 Gy, 2 H), 8.94 (4.1-1.8 Ne, I H); 19E NMR (acetone-db); -137.60; LC/MS: retention time: 26.19 minutes; purity: 89.9395; MS ( mass/charge): 279.06 s (Mne). 17126 M4-(4-acetoxyphenyl)-2-chloro-5-fluoro-4- Similar to the preparation of 2-chloro-sh4-(3,4-ethylenedioxyphenyl)-5- fluoro-4-pyrimidinamines (8940210) pyrimidineamine, M4-(4-acetoxyphenyl)-2-chloro-5-fluoro-4-pyrimidinamine are obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-acetoc cyaniline РХ/МС: « retention time: 25.97 minutes; purity: 9895; MS (mass/charge): 281 (MA 1N

NMR (SOSIS): 13 8.07 (IN, d, 12: 2.7 Hl), 7.64 (2H, b, 32 9 Hz), 7.12 (2H, f, 7-9 Hz), 7 ,00IN, 5), 2.31 (ZN, 5). шщ с 7.1.27 2-chloro-5-fluoro-M4-(4-hydroxyphenyl)-4- Similar to the preparation of 2-chloro-Х4-(3,4-ethylenedioxyphenine)-5-fluoro-4-pyrimidinamine (K940211) pyrimidineamine . LC/MS: and retention time: 20.10 minutes; purity: 9899; MC (mass/charge): 240 (MN);

IN NMR (SOSIS): 0 8.02 (IN, a, 12 2.7 Hz), 7.46 (2H, d, 1- 8.7 Hu, 6.86 (2H, y, 1-9

Hz), 6.85 (1, 5), 4.94 (1H, 5). 71.28 2-chloro-M4-(2,3-dimethyl-4" Analogously to the preparation of 2-chloro-M44(3,4-ethylenedioxyphenyl)-5-fluoro-4" (o c hydroxyphenyl)-5-fluoro-4-pyrimidinamine | of pyrimidine, 2-chloro-XH4-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidinamine (8949213) is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 2,3-dimethyl -4- co hydroxyaniline. LC/MS: retention time: 23.29 minutes; purity: 9395; MS (mass/charge): 268 (MNK; 1 N NAM (SOSISU: Gi 8001, a, 2- 2.7 Hz ), 7.16 IN, I, 1- 8.7 Gy), 6.68 (IN, 4, 1 8.7 Hz), 6.61 (1H, 5), 4.87 (1H, 5), 2.21 (ZN, 5), 2.16 (ZN, 5). -y (Se) 42) ko 60 b5

7425 2-chloro-M4-4(3-chloro-4-thihydroxy-5- Analogously to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-methiaphenyl)-5-fluoro-4- pyrimidineamine pyrimidineamine, 2-chloro-M4-(3-chloro-4-tihydroxy-5-methylphenyl-5-fluoro-4- (к94а230) pyrimidineamine is obtained as a result of the reaction of 2,4-lichloro-5-fluoropyrimidine and 3-chloro- 4-hydroxy-5-methylaniline. LC/MS: retention time: 26.26 minutes; purity: 9035; /H NMR (0OM50-46); GL 9.94 (1H, 5), 9.21 (IN, 5 ), 8.37 (1H, 4, 3.6 Hz), 7.68 (IN, 5y, 7.41 (1H, z), 2.30 (ZH, 5). 71.30 2-chloro-5-fluoro-M4 -14-13-04- Similar to the preparation of 2-chloro-ych4-(3,4-ethylenedioxyphenyl)-5-fluoro-4- morpholinopropid|oxyphenyl-4-pyrimidinamine, 2-chloro-5-fluoro-M4-(4- 13-(M-morpholinepropyl|oxyphenyl|-4-pyrimidinamine (5940247) pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-35-fluoropyrimidine and 4-(3-(M-morpholine)propyl|oxyaniline. LC/MS: duration retention: 17.15 minutes; purity: 9995; MS (mass/charge): 367 ""Mn.Yu; IN NMR (SOSIZ): HI 8.02 (1H, 4, 15 2.7

Hz), 7.49 (2H, 4, 1- 8.7 Hz), 6.92 (2H, y, 12: 9 Hud), 6.85 01, 5), 4.03 (2, 1-63 Go), 3.73 (AN, 61: 4.6 Gy), 2.53 (2H, 6 1-.6.7 Gy), 2.47 (AN, t), 1.98 (2H, t) . 71.31 Mm4-(2-(4-04-benzylpiperazine)ethyl)|-2- Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-chloro-5-fluoro-4-pyrimidnamine pyrimidineamine, M4-(2-14-O-benzylpierazine)stil|Y-2-chloro-5-fluoro-4- (8940259) pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 2- g4-( M-benzylpiperazine) stylamine. LC/MS: retention time: 21.11 minutes; purity: 9695; MS (masg/charge): 349 (M); IN NMR (SOSIZ); 7 7.88 (1H, a, 15 2.6

Hz), 7.31-7.17 (AN, t), 7.14 (1H, d, 1-51.7 Hz), 7.10 (IN, 5), 3.76 (2H, t), 3.24 (2H, t), 2.90 (2H, po), 2.59 (2H, t), 2.34 (2H, t), 1.76 (4H, t). 7.1.32 M4-(3-tert-butylhexyl)-2-chloro-3-fluoro- Analogous to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-4-pyrimidinediamine (K940268) pyrimidineamine , M4-(3-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-tert-butylamine. LC/MS: retention time: 33.96 minutes; purity: 98 90; MS (mass/charge: 279 (M); IN NMR (SISISU: O 8.05 (IN, 4, 1-3 Hz), 7.62 1H, 321.3

Go), 7.50 1, tu, 7.34 (1H, 6, 3e 7.6 Si), 7.22 (IN, t), 6.96 (18, 50), 1.34 (9H, 5 ). 7133 ?-chloro-5-fluoro-MA-I3- Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-(hydroxymethyl)phenyl|-4-pyrimidinamine | of pyrimidine, 2-chloro-5-fluoro-M4-(3-(hydroxymethyl)phenyl| 4-pyrimidinamine (5925756) is obtained as a result of the reaction of 2,2-dichloro-5-fluoropyrimidine and 3-aminobenzyl alcohol. IN NMR (SOSIS) ; 118.45 (B5, 1H), 7.96 (d, 1H, 3- 2.9

Hz), 7.654, 1H,3: 8.2 Gy), 7.34 (5, 1NH, 7.31 (1 H, 3: 8.2 Hz, 7.07 (0, 1H, 158.2

HC), 4.52 (8, 2H) 3; 192 YAM? (SOSIZU: -44394 (5, 12); RHLIS: retention time: 20.29 minutes; purity: 100 95; MS (mass/charge); 254 (MN). 7.1.34 2-chloro-5-fluoro-M4 -|4- Analogous to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4- c (hydroxymethyl)phenyl|-4-pyrimidinamine pyrimidineamine, 2-chloro-3-fluoro-M4-(4 -(hydroxymethyl)phenyl|-4-pyrimidinamine (4K925759) is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-aminobenzyl alcohol. Hz), 7.62 (d, 2H, 1- 9.0 Hz), 7.40 (y, 2H, 1- 8.1 Gy), 6.99 (5, 1H), 4.70 (5, 2H); 1I9E NMR (SOSIS): - 44570 (5, IR), LC/MS: retention time: 19.57 minutes; purity: 9998; MS (mass/mass): 254 (MNK). (Che) 7.1.35 2-chloro -M4-(3,3-dihydroisobenzofuranyl- | Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-1-on-6-yl)-5-fluoro-4-pyrimidinamine pyrimidinamine . 6 a.m ino-3,3-dihydroisobenzofuran-1-one-. РХ/MIS: duration of detention: "-- 21.15 minutes; purity: 94.7 95; MC (mass/charge): 280 (MN). 7.1.36 2-chloro-5-fluoro-M4-4(2K)-hydroxy-(15)- Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenia)-5-fluoro-4-Ha methyl-2 -phenylethyl)-4-pyrimidinamine pyrimidineamine, 7-chloro-5-fluoro-1х4-((2К)-hydroxy-(15)-methyl-2-phenylethyl)-4-(К925762) pyrimidineamine is obtained as a result of the reaction 2,4 -dichloro-5-corpyrimidine and

From (18,25)-(-)-norephedrine. 1H NMR (SOSISU: 01 7.85 (8, 1H, 1- 3.0 Gy), 7.38 (t, 58), (Ge) 5.554, 1H, 3- 7.5 Hz), 5.00 ( 4, IN, 7: 3.0 Hz), 4.54 (t, 1H), 2.87 (B5, IN), 1.10 (9, 1H, 1- 6.9 Gy); 195 NMR (SOSISU: -44408. 7.137 M-(2-chloro-b-ethoxycarbonyl»5-nitro-4- Analogously to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenia)-5-fluoro-4-pyrimidinyl) pyrimidine glycine ester, M-(2-chloro-b-ethoxycarbonyl-5-nitro-4-pyrimidinyl) glycine ethyl ether 4(К925850) is obtained as a result of the reaction of 2,4-dichloro-6-stoxycarbonyl-5-nitropyrimidine and of the hydrochloride salt of glycine ethyl ether. 1 Hy), 1.40 (ZA, ssh 1-6.9 Hz), 1.33 (0, ZN, le 7.2 Hz); LC/MS: retention time: 28.27 minutes; s purity: 97925 ; MS (mass/charge): 332 (M Ю). n 7.1.38 2-chloro-5-fluoro-M4A-(2-hydroxy-2" Analogous to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl) -5-fluoro-4- and » phenylethyl)-4-pyrimidinamine (8925763) | pyrimidinamine, 2-chloro-5-fluoro-M4-(2-hydroxy-2-phenylethyl)-4-pyrimidinamine is obtained as a result of reaction 2, 4-dichloro-5-fluoropyrimidine and 2-amino-1-phenylethanol. 1H NMR (SOSIS); (17.88 (y, TE, 7- 3.0 Hn), 7.41-7.32 (t, 5 ), 5.71 (p5, 1NU, 4.97 (9, 1H, 1-81 Hz), 3.98 (t, IN), 3.56 (t, 1H), 2.57 (5, 1H); 19E NMR "SOSIZ");: -45149; LC/MS: retention time: 22.27 minutes; purity: 9890; MS (ee) (mass/charge); 263 (M). 71.39 2-chloro-5-fluoro-Ma-(furfuryl)-4- Similar to the preparation of 2-chloro-Ma(3,4-ethylenedioxyphenyl)-5-fluoro-4- kz pyrimidinediamine (KO25764) pyrimidineamine, 2-chloro-5 -fluoro-M4-(furfuryl)-4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and furfurylamine. IN NMR - (SOSIZ)U: 87.91 (4, IN, 15 1.8 Hyd), 7.39 (9, 18, 72 1.2 Hz), 6.35 (t, 2H), 5, 50 (b5, 1), 4.69 (4, 2H, 1e 5.1 Hn); 19E NMR (SOSIZ): -45163; РЧ/МС: duration of retention: (Се) 42) ko 60 b5

ASHES 24.52 minutes each; purity: 9795; MS (mass/charge): 228 (MK). 7.1.40 935010: (-)-2-chloro-35-fluoro-M4-11-(4- Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-tihydroxyphenia)stil| -4-pyrimidinediamine pyrimyldynamine, C)-2-chloro-5-fluoro-M4-I(4-tihydroxyphenyl)ethyl)-4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine with I-(4- hydroxyphenyl)stilamine. IN NMR (SOSIZ)U: 6 7.88 a, 19, 1-2.3 Hz), 7.50-7.47 s (840, 2Н, 1-1.7 and 8.7 Hz), 7, 26-7.23 (49, 3-2: 8.7 and 1.7 Hz), 5.35-5.28 (t, 2H), 1.59 (y,

ЗН, /: 70 Hz). 7141 K935011: (SEN 4(4-bromophenyl)ethyl)- | Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4- 2-chloro-5-fluoro-4-pyrimidinamine pyrimidineamine, ()-M4-(11-4(4-bromophenyl)ethyl |-2-chloro-5-fluoro-4-pyrimilinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 1-444-bromophenyl)ethylamine. IN NMR (SOSIZ): 5 7.88 (y, 1H, 7-2 2.3 Hz), 7.49 (4, ZN, 2 70 8.7 Hz) 7.25 (0.2H, 3: 8 .7 gy), 5.45-5.726 (t, 2H), 1.59 (8, ЗН, 727.0 Hz). 7.142 8935007: 2-chloro-5-fluoro-MA-11-1(15)- Similar to the preparation of 2-chloro-M4-(3,4-styrenelyoxyphenyl)-5-fluoro-4-phenylethyl-4-pyrimidinamine, 2 -chloro-5-fluoro-M4-P1-((15)-phenyl|ethyl|-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 14415)» phenylethylamine. 18 NMR (SOSIS): 5 7.86 (a, 1Н, 3 -2.9 Hz), 7.37 (4.4Н, 1-47

Hz), 7.34-7.30 (t, 1), 5.50-5.32 (t, 2), 1.62 (0, ZN, 16.6 Hn); LC/MS: retention time: 29.5 minutes; purity: 9892; MS (mass/charge): 252 (MN). 71.43 KkUZ5008: 2-chloro-5-fluoro-M4411-(К1К)- Analogously to the preparation of 2-chloro-144-(3,4-styrenedioxyphenyl)-5-fluoro-4-phenylethyl-4-pyrimidinamine, 2-chloro- 5-fluoro-M4-(1-((1K)-phenyl|ethyl)-4-lyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 1401K)-phenylethylamine. IN NMR (SOSIZ): 5 7.87 (4, 1H, 7 -2.9Esh), 7.374, NN, 7-41

Hz), 7.34-7.30 (t, 1H), 5.38-5.31 (t, 2H), 1.62 (9, ЗН, 3 - 6.4 Gy). 7144 K935012: 2-chloro-Ma-Idi (3,5-Di Analogous to the preparation of 2-chloro-1х4-(3 d-styrenedioxyphenyl)-5-fluoro-4-"trifluoromethyl)phenyl)|methyl|-5-fluoro- 4- | pyrimidine, 2-chloro-M4-(di(3,5-di (trifluoromethyl)phenyl)|methia|-5-fluoro-4-pyrimidinamine pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine with di!3 ,5-distrifluoromethyl)phenyl|methylamine. IN NMR (SOSIZU: 6 8.06 (0, 1H,1- 2.3 Gy), 7.92 (5, 2H), 7.74 (8, 4H), 6.75 (4, 1H, 32 7 .6 Gy), 5.80 (4, 1, 3-70 Hn). 741.45 vZ35014: 2-chloro-5-fluoro-M4-Y-C1K)-4- Similar to the preparation of 2-chloro-M4-43.4 -ethylenedioxyphenyl)-5-fluoro-4-methoxyphenylethyl|-4-nyrimidineamine of pyrimidine, 2-chloro-5-fluoro-M4-4114(18)-4-methoxyphenylethyl|-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro -5-fluoropyrimidine with (K)-(k)-1-(4- methoxyphenyl)ethylamine. a, 2H, sem 1-: 8.8 Gy), 6.89 (0, 2H, 12 8.8 Gy), 5.39-5.26 (t, 20), 3.80 (5, ЗН) , 1.59 (4, ZN, 4-64 th). on 7.1.46 k935015: 2-chloro-5-fluoro-M4-11-(15)-4- Similar to the preparation of 2-chloro-5-fluoro-M4-(3,4-ethylenedioxyphenyl)-4-methoxyphenyl|ethyl )|-4-pyrimidinamine pyrimidineamine, 2-chloro-5-fluoro-M4-|1-К15)-4-methoxyphenyl|ethyl|-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine with (5 )-(-)-14(4-methoxyphenyl)ethylamine. IN NMR (SOSIZ): 6 7.85 (y, 1H, 3-23 Gy) 7.31 (y, 2H, (Che) 1- 8.8 Gy), 5.89 (y, 2H, 2- 8 .8 Hz), 5.38-5.29 (t, 21), 3.80 (5, ZN), 1.59 (y, ZN, 157.7 g). (22) 7.1.47 8935013: 2-chloro-M-(fluoren-9-yl)-5- Analogous to the preparation of 2-chloro-M-(3,4-ethypendioxyphenyl)-5-fluoro 4-fluoro-4-pyrimidinamine pyrimidinamine . IN NMR (SOSIZU: o 7.97 (0, 1H, 1: 2.5 Gy), 7.73 (4.2, 7.6 Hz), 7.59 (4, 2H, 1 7.6 Hz) . , 5.45 (4.1H, 3-8.4 Go).

From 7.1.48 8935210; 2-chloro-5-fluoro-M-(1- Analogous to the preparation of 2-chloro-h-(3,4-ethylenelioxyphenyl)-5-fluoro-4- co (methoxycarbonyl)methyl-indazolin-o-yl|- pyrimidineamine . -46); 510.17 (5, IN), 8.33 (4, 1H, 1- 3.5 Hz), 8.05 (in, NI, 7.91 (5, 1H), 7.74 ( 0, IN, 1- 8.2 Hz), 7.50 (d, IN, 1- 7.6 Hn). 5.31 (z, 2), 3.66 (z, ZN). « 1.1.49 K935200: 2-chloro-5-fluoro-M-(1-methyl- Analogous to the preparation of 2-chloro-MSH4-(3,4-ethylenedioxyphenyl)-5-fugor-4--o indazolin-5-yl)-4- pyrimidine: pyrimidine, 2-chloro-5-fluoro-N-(i-methyl-indazodin-5-yl)-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 5-amino-1- methyl-indazoline. 1H NMR (2M50-y06): 510.01 (5, 1NH, 8.27 (y, 1H, 3-3.5 Hn), 85.04 (0 1H, n » 1-1.7 Go), 7.98 (4, 1H, 2- 1.7 Hz), 7.644, 1H, 1- 8.8 Go), 7.56 (49, 1, ge 1.7 and 8.8 p Gy), 4 ,02 (5, ZN). PH/MS: retention time: 21.72 minutes; purity: 9995; MS (mass/charge): 278 (MN V). 7.1.590 K935017: M-(5-bromo-2- Similar to the preparation of 2-chloro-M4-3,4-ethylenedioxyphenyl)-5-fluoro 4-chloropyrimidinyl)-4-fluorophenylethylamine | of pyrimidine, M-(5-bromo-2-chloropyrimidinyl)-4-fluorophenylethylamine is obtained as a result of the reaction of 4-fluoro-(2-methylbenzamine) and 5-bromo-2,4-dichloropyrimidine.

IN NMR (SOSIZU: 6 8.12 (5, 18), 7.35-7.25 (Fi, 2H, 1- 3.5 and 8.7 Gy), 7.05 ( 1H, 3- ko 8, 7 Gy), 5.63 (0, 1H, 4- 6.4 Gy), 5.36 (49, IN, 1H, 7: 6.4 and 7.0 Go), 1.60 (y, ZN, 1-7.0

Gy); LC/MS: retention time: 30.73 minutes; purity: 9495; MS (mass/charge): z31 (Mn. -y 7.1.51 Kk935009: (4)-M-(2-chloro-5- Analogous to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro 4- "about 50 la ZI pyrimidineamine, ()-M-(2-chloro-5-fluoropyrimidine I). 1-(4-fluoropheny)stilamine 42)

F) ko 60 b5 fluorophenyl)stilamine is obtained as a result of the reaction of 4-fluoro-α-methylbenzylamine and 2,4-dichloro-5-fluoropyrimidine. IN NMR (SOSIZ); 6 7.87 (d, 1H, 7- 2.3 Gy), 7.37-7.33 (ad, 2H, 1- 5.4 and 5.4 Gy), 7.04 (6 2H, 7: 8.4 Gy), 5.35-5.31 (t, 2NI), 1.60 (d, ZN, 1: 6.4 Hp);

LC/MS: retention time: 32.90 minutes; purity: 9595; MS (mass/charge); 270 (MN). 7.1.52 8935022: 5-bromo-2-chloro-14-14-(M- Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-methyl-2-methoxycarbonyl)ipyrrolyl)- 4-pyrimidinamine, 5-bromo-2-chloro-M-(M-methyl-2-carbomethoxypyrrol-4-yl)-4-pyrimidinamine Pyrimidinamine is obtained as a result of the reaction of 5-bromo-2,4-dichloropyrimidine and M-methyl- 2-carbomethoxy-4-aminopyrrole hydrochloride with the addition of diisopropylethylamine. IN NMR (SOSIZ): 6 8.21 (5, IN), 7.43 (0, 1H, 1-1 Gu, 7.13 (bg5, IN), 6.84 (4, IN, 1- 1, 8 Go), 3.95 (5, ZN), 3.82 (5, ZN); LC/MS: retention time: 26.96 minutes; purity: 9195; MS (mass/charge): 346 (MN). 7.1.53 Ke35234: 2-chloro-5-fluoro-M4-(4-(3-phenyl- | Similar to the preparation of 2-chloro-m4-(3,4-ethylenedioxyphenyl)-5-fluoro-4- 1,2, 4-oxadiazol-5-pyrimidinamine, 2-chloro-5-fluoro-Ma-(4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl-4-pyrimidinaminyl)methyleneoxyphenyl|-4- pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 5-4-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole. IN NMR (PM50-46): 5 9.92 (5, 111 ), 8.26 (8, NN, 7 3.5 Hz), 8.02-7.99 (t, 2Н)), 7.60-7.56 (tp, 5НУ 1 (а, 2Н, 21 88 Hn), 5.58 (5, 2H); LC/MS: retention time: 32.09 minutes; purity: 9625; MS (mass/charge): 398 (MN). 12 71.54 8935235: 2-chloro-5- fluorine-M4-14-(3-methyl- 5-fluoro-M4-(4-(3-methyl-1 ,2,4-oxadisol-5-yl)methyleneoxyphenyl|-4-pyrimidinamine yl)methyleneoxyphenyl)-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 5-(4-aminophenoxymethyl)-3-methyl -1,2-4-oxadiazole. IN

NMR (PM5O0-46): 8 9.91 (5, 1H), 8.26 (f, 1H, /e« 3.5 Go), 7.56 (4, 2H, 72: 8.8 Hz), 7.05 (94, 2H, 12 8.8 Gm), 5.46 (5, 2H), 2.34 (5, ZNU; РХ/MS: retention time: 25.05 minutes; purity: 9890; MS ( mass/charge): 336 (MN). 7.1.55 8935236: 2-chloro-5-fluoro-M4-14441- Similar to the preparation of 2-chloro-M4-(3,4-ethyleneoxyphenyl)-5-fluoro-4-ethoxycarbonyl - I-methyl)stylyphenyl-4-pyrimidinamine, 2-chloro-5-fluoro-M4-1441-ethoxycarbonyl- I-methyl)ethylIphenyl-4-pyrimidinamine pyrimidineamine is obtained as a result of the reaction of 2,4-lichloro-5-fluoropyrimidine and 4 - (1-stoxycarbonyl-1-methyl)ethylaniline. 18 NMR (050-946): 5 9.99 (5, 1H), 8.30 4, 1H, 7: 3.5 Hz), 7.50 (0, 2H, 3: 8.8 Gy), 7 .30 (4, 2H, 3 8.8 G i), 4.04 (46, 2H, 1-70

Gi), 1.47 (5, 6), 1.10 (, ЗН, 72 7.0 Hz); РХ/MS: holding time: 31.07 He minutes; purity: 974; MC (mass/charge): 338 (MN). 29 7,A-dichloro-5-ethoxycarbonylpyrimidine A dry reactor with a stirrer and an irrigated condenser is filled with 5-He)ethoxycarbonyluracil (1.84 g, 10 mmol), ROSIZ (10 ml) and MM-dimethylaniline (1 ml) and heated at 90 oC for 2 hours. Excess ROSIZ is removed under reduced pressure and quickly cooled with ice water (190 g). The aqueous solution is extracted with ethyl alcohol (3 x 100 ml), washed with a saturated aqueous solution of Mansoz and water (but 100 ml each). (se)

After drying over sodium sulfate, the ethyl ether is removed, and the residue is dried in a deep vacuum to give 2,4-lichloro-5-He»! ethoxycarbonylpyrimidine. IN NMR (SOSIS): 6 9.00 (5, 1H), 4.45 (a, 2H, 7: 6.9 Hz), 1.42 (i, ZN, 2: 6.9 Gy). 7.1.57 -(2-chloro-5-ethoxycarbonyl-4-Ethyl ether mixture of I-phenylalanine hydrochloride (0.137 g, 0.6 mmol), 2,4--pyrimidinyl)-ethyl ether I. dichloro-5-ethoxycarbonylpyrimidine (0.112 g, 0.5 mmol), tristylamine (0.7 ml, 0.6 s phenylalanine (K926518) and M-(4-chloro-5- | mmol) in TIF (tetrahydrofuran) (4 ml) are heated in sealed tube at 100 ethoxycarbonyl-2-pyrimidinyl)-ethyl | oC for 3 hours. The reacted mixture is dissolved in H2O (20 ml), the ether of I.-phenylalanine (5926519) is liberated with the help of CHNOCI2 (3 x 50 ml), washed with a solution of 2M HC (10 ml) and water (c) (10 ml), and evaporated solvent. The obtained residue is purified by means of preparative TLC, using a 1525 solution of EtOAc in hexane to obtain two products, namely M-2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-ethyl ether of I.-phenylanine (K926518). YIN YAM? (SOSIZ): 6 8.72 (0.18, 3- 6.92 gy), 5.66 (5, 1), 7.32-7.17 (t, 5NI), 5.05 (44, 1 ,21, and 5.7 Gy), « 4.34 (Ff 2H, 1- 6.9 Hz), 4.20 (4, 2H, 1- 5.1 Gy), 3.24 (94, IN, 2: 5.4 Gy), 3.16 (44, 19, 157.51), 1.35 ZA, i 7.2 Hz), 1.24 (i, ЗН, 72 7.2 Hz); LC/MS: retention time: 37.15 minutes; purity: 9995; MS (mass/charge): 378 (MH) and M-(4- - s chloro-5-ethoxycarbonyl-2-pyrimidinyl)-ethyl ether and.-phenylalanine (K926519). IN NMR (SOSIZ): 6 8.83 (5, 1H), 7.28 (t, ЗН), 7.18 (t, 2H), h z» 6.00 (B 1H), 4.99 (Bdo, 1 ), 4.36 (d, 2H, 2- 7.8 Gy), 4.19 (d, 2H, 7- 6.9 Hz), 3.20 C, " 2A, 126.9 Gy). 1, 38 (0 ZN, 124.5 Go), 1.24 (6 ZN, 1256 Hz); RHUMS: retention time: 34.80 minutes; purity: 8895; MS (mass/burn): 378 (Mk). 7.1 .58 M-(2-chloro-5-stoxycarbonyl-4- Analogous to the preparation of M-(2-chloro-5-stoxycarbonyl-4-pyrimilinyl)-ethyl pyrimidinium)-ethyl ether I.-valine ether I.-phenylalanine, M -(2-chloro-5-ethoxycarbonia-4-primidinyl)-ethyl ether 1.- (ee) 48926520) and M-(4-chloro-5-valine (8926520) are obtained as a result of the reaction of 2,4-dichloro-5 - ethoxycarbonyl-2-pyrimidinyl)-style | ethoxycarbonylpyrimidine and ethyl ether and -valine. IN NMR (SOSIS): 5 8.80 ko ether I.-valine (8926521) (y, 1, - 8.1 Hz), 8 .68 (5, 1H), 4.77 (64, 1H, 1- 4.8 Hn), 4.36 (d, 2H, /- 7.2 Gy)u, 4.24 (9, 2H, 1 : 6.6 Hz), 2.38 (t, IN), 1.39 (i, ZN, 4- 6.9 Hz), 1.29 (i, ZN, 1- 7.2 Go), 1, 03 (dF, ZN, 1" 3 Ha), 1.00 (9, ZN, 72 2.7 Hz); LC/MS: duration of detention: 36.54 -- minutes; purity: 8995; MC (mass/charge): 330 (MN). M-g4-chloro-5-ethoxycarbonyl-2-pyrimidinyl)-ethyl ether of 1.-valine (2926521) is also synthesized. IN (se) NMR (SOSIS): 5 8.82 (5, 1H), 6.02 (t, IN), 4.69 (44, 1H. /- 4.8 and 4.5 Gy), 4, 33 (9, 42) (F, ko 60 b5

2H, 0-75 Cy), 4.23 (4, 2H, 1-7.5 Gy), 2.28 (IN grains). 1.34 (, ZN, 2- 6.9 Hz), 1.28 zn, I1-7 Go), oo sa, bnN, A 7.2 Hz); LC/MS: retention time: 33.53 minutes; purity: 9195; MS (mass/charge): 330 (Mk). 7.1.59 1442-chloro-5-ethoxycarbonyl-4- Analogous to the preparation of IM-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-stylopyrimidinyl)-ethyl ether of I.-leucine ester of I.-phenylalanine, M-( 2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-stil ether (8926522) And leucine is obtained as a result of the reaction of 2,4-dichloro-5-ethoxycarbonylpyrimidine and ethyl ether of leucine. , IN), 8.64 (4, IN, 7.8

Hz), 4.84 (z, 1Н), 4.38 (d, 2АН, 1-7.2 их), 3.75 (в, ЗН), 1.73 (t, 2Н), 1.39 ( and, ZN, 15 6.9

Ti), 0.97 (d, ZN, 1-:4.2 Hz), 0.95 (d, ZN, 224.8 Hz); PH/MS: retention time: 36.09 minutes; purity: 92; MC (mass/charge): 330 (MN). 71.60 МА2-chloro-5-ethoxycarbonyl-4- Analogous to the preparation of M-(2-chloro-ethoxycarbonyl-4-pyrimidinyl)-ethyl pyrimidinyl)-stilyl ether of i.-alanine of I«-phenylalanine ester, M-(2-chloro- 5-ethoxycarbonyl-4-pyrimidinyl)-stilyl ether (KO926523) and M-(4-chloro-5-I.-alanine (К926523) are obtained as a result of the reaction of 2,4-dichloro-5-ethoxycarbonyl-2-pyrimidinyl)- Ethylon | stooxycarbonylpyrimidine and ethyl ether of I--valine. 1H.NMR (SOSIS): 5 8.80 1.-alanine ether (K926524) (Ba, 1NI), 8.68 (5, IN), 4.79 (d, IN, 3-7.2 Hz), 4.35 (F, 2H, 1 7.2 Gy), 4.4 (t, 2H), 1.53 (4, ЗН, 1-:7.2 Сy), 1.38 (, ЗН, 1- 7.2 Pich), 1.29 (, ZN, 17.2 Hz); RF/MS: retention time: 31.89 minutes; purity: 9496, MS (mass/charge): 303 (MN...

M-(4-chloro-5-ethoxycarbonyl-2-npyrimidinyl)-ethyl ester of I.-alanine (K926524) was also synthesized. IN NMR (SOSIS): 6 8.80 (c, 1H), 6.01 (5, 1H), 4.65 (Ba, 1H), 4.35 (a, 2H). 4.20 (ad, 2), 1.55, 1, ZN), 1.40 (6, ZN), 1.25 (I, ZN); LC/MS: retention time: 28.78 minutes; purity: 8490; MS (mass/charge): 302 (M'-) 761 2-chloro-M4-(4-pebutyloxyphenia)-5-fluoro- | To a solution of 2,4-dichloro-5-fluoropyrimidine (0.5 g, 3.0 mmol) and 4-p-butoxyaniline 4-pyrimidinamine (0.49 g, 3 mmol) in acetone LH?O (1:9 ml ) at room temperature, pour concentrated hydrochloric acid (0.1 ml). The mixture is heated in a reflux flask for 1 hour, cooled to room temperature and transferred to alkaline solution by adding 2M solution of MaOH (2 ml). The aqueous layer was removed with EtOAc (2 x 50 mL) and the combined organic extracts were dried (Ma2504), filtered and concentrated in vacuo.

The crude black solid residue was purified by chromatography (4:11 hexane/E(U As) to give 2-chloro-M4-(4-p-butyloxyphenyl)-5-fluoro-4-pyrimidinamine (0.71 g, 8095 ) in the form of brown oil: IN NMR (300

Mhz, SOSI3) 6 8.01 (4, 2-2.7 Si, 1H), 7.51-7.46 (t, 2H), 6.95-6.89 (t, 2NI), 6.83 (5,

IN), 3.99-3.95 (52 - 6.5 Hz, 2H), 1.82-1.57 (t, 2H), 1.53-1.43 (t, 2H), 0.98 (63-72 Ha!

Hz, ZN). ---- - t 2-chloro-M4-(4-n-hexyloxyphenyl)-5-fluoro- | Similarly to the preparation of 2-chloro-M4-(4-p-butyloxyphenyl)-5-fluoro-4-He) 4-pyridinamine pyrimidineamine, 2-chloro-1h4-(4-n-hexyloxyphenyl)-5-fluoro-4- pyridinamine is obtained as a result of resection of 2,4-dichloro-5-fluoropyrimidine with 4-n-hexyloxyaniline. The crude product is purified by chromatography (4:1

SNCIUKUAs) in order to obtain (14) (0.74 g, 7695) in the form of red- (Che) brown oil, which hardens over time: EN NMR (300 MG, SOSIZ) 5 8.01 (6.1 t- 2.7 Hz, IN), 7.50 (4.12 9.0 Hz, 203), 6.92 (4.1 «9.0 Gy, 7H), 6.84 (Be, 1H), 3, 96 (i, b - 6.5 Hz, 2H), 1.83-1.74 (pz, 2H), 1.48-1.41 (t, 28), 1.36-1.34 (t, 4H), 0.93-0.89 (t, zn). 7.1.63 M44(3-benzyloxyphenyl)-2-chloro-4- Sums of 2,6-dichloropyrimidine (2.00 g, 13.4 mmol), 3-Bbenzyloxoaniline (2.07 g, -- pyrimyldynamium 13.4 mmol ) and chrystylamine (2.72 g, 26.8 mmol) in 1-butanol (20 ml) were heated at 50 C for 17 hours. The reaction mixture is concentrated to remove most of the 1-butanol, after which the crude product 3B is pre-absorbed on silica gel using chloroform and purified by flat chromatography (95:5 chloroform/methanol) to obtain M4-(3-benzyloxyphenyl) )-2-chloro-4-pyrimidinamine (1.70 g, 4095) in forms; colorless oil: IN NMR (300 MGy, PM5O (dimethyl sulfoxide 3-46) 510.2 (5, 180), 8.16 (a, 1-6.0 Hn, 15), 7.48-7.24 (t , 7H), 7.12 (4.72-9.0 her, 1H)), 6.78 (t, 2H), 5.11 (in, 28);

EBI MS mass/charge 312 (С17Н14СЯМ3О - NIK. « 7.3.54 M4-14-(tert- Analogously to the preparation of M-(2-chloro-5-stoxycarbonyl-4-pyrimidinyl)-ethyl butoxycarboniamethyleneoxy)phenyl|-3- ether 1 -phenylalanine, M4-(4-(tert-butoxycarbonylmethyleneoxy)phenyl|-3-chloro-5-chloro-5-ethoxycarbonyl-4-pyrimidinamine | ethoxycarbonyl-4-pyrimidinamine is obtained as a result of the reaction of 5-carboxyethoxy- - with (5926578) 2,4-dichloro pyrimidine and tert-butyl 4-aminophenoxyacetate. LC/MS: MS (mass/charge): 407 (MH). 7.3.65 Ma4-(4-ethoxyphenic)-5-ethoxycarbonyl-2- | Analogously to the preparation of M-(2-chloro-5-ethoxycarbonyl-4-pyrimidinyl)-ethyl trifluoromethyl-4-pyrimidinamine ester I.--phenylalanine, M4-(4-stoxyphenyl)-5-ethoxycarbonyl-2-trifluoromethyl-4- (8926059) pyrimidineamine is obtained as a result of the reaction of 4-chloro-5-ethoxycarbonium-7-trifluoromethylpyrimidine and 4-ethoxyaniline.IN NMR (SOSIS): 6 10.39 (in, 18), 9.07 (5, 1H), 7 ... 5 Gy), 4.06 (0, 2H, 2- 7.2 Gy), 1.44 (t, NU; LC/MS: retention time: (ohm) 38.49 minutes; purity: 10095; MS (mass/charge): 356 (MN). ka 7.1.66 M2-(4-ethoxyphenia)-5-methoxycarbonyl-4-th Similarly to the preparation of IM-(2-chloro-5-stoxycarbonyl-4-pyrimidinyl)-style trifluoromethyl-2-pyrimidinamine ester of I-phenylalanine, M2- (2-ethoxyphenyl)-5-methoxycarbonyl-4-trifluoromethyl-2- (К926060) pyrimidineamine is obtained as a result of the reaction of 2-chloro-5-methoxycarbonyl-4-"se 20 "VI M5- mass spectrometry with ionization in electrospray ( perekl) 42) ko 60 b5 of trifluoromethylpyrimidine and 4-ethoxyaniline. IN NMR (SOSIS): 5 8.98 (5, 1H), 7.47 (t, 3), 6.91 144, 2H, 34-:2, 1 x 6.9 Hz), 4.05 (4, 2H, 6.9 Gy), 1.42 0, ЗН, 1- 6.8 Hz); 19E NMR (SOSIZ3): -19105; PH/MS: retention time : 33.87 minutes; purity: 10095; MS (mass/charge: 342 (MNE). 7.167 2-Chloro-5-fluoro-Ma-Y3-(1H-tetrazole-5-) A reactive sumnv containing 2,4- dichloro-5-fluoro-pyrimidin n equivalents) and 3-iluphenyl|-4-pyrimidinamine (8926853) (tetrazol-5-yl)aniline (1 equivalent) in a solution of methanol in water (1:1 by volume), heated at 60 oC for 24 hours After dilution with water and acidification I, the formed solid fraction is filtered, washed with water, dried and analyzed to obtain 2-chloro-5-fluoro-144-13-(TH-tetrazole-5-iluphenyl-4-pyrimidinamine (K926853). Alternatively, this reaction can be carried out by treating 2,4-dichloro-5-fluoropyrimidine (1 equivalent) with 3-(tetrazol-5-yl)aniline (C equivapent) in a solution of 70 methanol in water (1:1 by by volume) at 60 oC for 2-3 hours, or at room temperature for 24 hours in order to form 2-chloro-5-fluoro-M4-I341H-tetrazole-5-ilyphenyl|-4-pyrimidinamine. TN NMR (0М50О-46): 85 10.25 (5, IN), 8.43 (5, 1Н), 8.37 (b, 1Н, 1 3.6 Std), 7.90 (da, IN, 1- 0.9 and 9 Hz), 7.75 (0, 1H, 1-7.5 Gy), 7.61 (6 1H, 2: 7.8 Hz; LC/MS: purity: 9095; MS (mass/ charge): 292 (MH). 7168 2-chloro-M4-2,5-dimethoxy-4-chlorophenyl)- | Similarly to the preparation of 2-chloro-5-fluoro-M4-(3-(1 H-tetrazol-5-yl)phenyl|-4-5-fluoro-4-pyrimidinamine (K926858) pyrimidineamine, 2-chloro-M4-(2 ,5-dimethoxy-4-chlorophenyl)-5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidic with 2,5-dimethoxy-4-chloroaniline. LC/MS: purity: 9795; MS (mass/mass): 316 (M-2H) apa 320 (min). 7469 2-xpro-5-fluoro-M4-(3-methoxycarbonyl-5- | Similar to the preparation of 2-chloro-5-fluoro-M4- (3-(1H-tetrazol-5-yl)phenyl-4-trifluoromethylphenyl)-4-pyrimidinamine, 2-xpor-5-fluoro-M4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-4- (K926861) pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro"3-fluoropyrimiline with 3-methoxycarbonyl-5-trifluoromethylaniline. IN NMR (SRZOB): δ 8.60 (5, 1H), 8.43 (5.10, 8.20 (0.19, 4-3 Gy), 7.99 (5, 1H), 3.96 (5, ZNU; 1942 NMR (SOZOYUU: -18332, - 18374; and -44259; LC/MS: purity: 9125; MS (mass/charge): 350 (MH). 7.41.70 2-chloro-5-fluoro-ma-I3-(2-phenyl-1,3,4-) Similar to the preparation of 2-chloro-5-fluoro-M4-13 -11H-tetrazol-5-yl)phen yl|-4-oxadiazol-5-yl)phenyl)-4-pyrimidinamine | pyrimidineamine, 2-chloro-5-fluoro-M4-(3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl)-4- (К926869) pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro -5-fluoropyrimidine with 3-(2-phenyl-1,3,4-oxadiazol-5-yl)aniline. 113 NMR (OM50-4y6): 5 10.28 (5, 1H), 8.62 (5, IN), 8.39 (y, 1H, 32: 3.3 Gy), 8.11 (t, 2H ), 7.98 (Bad, 1H, 75 6.9 Hz), 7.88 (Ba, IN, 1-2 VA Hz), 7.65 (t, 4H); RHLMS: purity: 7695; MS (mass/charge): 7695. sem 7 o 7.171 2-chloro-M4-I3-4(2-ethoxycarbonylmethylene- | Analogous to the preparation of 2-chloro-5-fluoro-Ma-I341H-tetrazod-z-yl)phenyl| -4- 1,3,4-oxadiazol-5-yl)phenyl-5-fluoro-4-pyrimidinamine, 2-chloro-M4-|3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazole-5- pyrimidineamine (KU26873) isophenyl-5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-(2-ethoxycarbonylmethylene-1,3,4-oxadiazol-5-yl)aniline, 1H

NMR(SOZOB);: 5 8.42 (, 1H, 22 1.8 Go), 8.19 (4, 1H, 1-3.3 p), 7.99 (46 1H, 421.2 and 8, 1 Gy), 7.82 (y 1H, 11.2 and 8.1 Hz), 7.58 (y, IN, re 9 Gy), 4.24 (9, 2H, 1- 3.9 (Che)

Ha), 4.17 (in, 2NI), 1.28 (6 ZN, 7-7.2 Gy); LC/MS: purity: 85956; MS (mass/charge) in: 379 (MNE). Those! 7.172 2-chloro-5-fluoro-M4A-(4- Similar to the preparation of 2-chloro-5-fluoro-M4-(341H-tetrazol-5-yl)phenia | 4-trifluoromethoxyphenyl)-4-pyrimidinamine | of pyrimidine, 2-chloro-5-fluoro-M4-(4-trifluoromethoxyphenyl)-4-pyrimidinamine h-: (8926875) is obtained as a result of the reaction of 2,4-dichloro-3-fluoropyrimidine with 4-trifluoromethoxyaniline. IN NMR (SOSIZ): 6 8.11 (9, 1, 2: 2.1 Hz), 7.68 (ad, 2H, 1-24 and 7.6 Hz), 7.26 (44, 2H, 72: Z ap 8.7 Gy), 7.0 (65, TN); 19E NMR (SUOZOIU): GI s -16517 apa -44523; LC/MS: purity: 9455; MS (mass/mass): 308 (MN). 71.73 2-chloro-z«rtor-M44(4) Similar to the preparation of 2-chloro-5-fluoro-M4-413441 H-tetrazol-5-yl)phenyl|-4-s trifluoromethylphenyl)-4-pyrimidinamine pyrimidinamine, 2- chloro-5-fluoro-M4-(4-trifluoromethylphenyl)-4-pyrimidinamine (K926876) is obtained as a result of the reaction of 2,4-dichloro-3-fluoropyrimidine with 4-trifluoromethylaniline. IN YMR (SYUSIZ): PO 8.15 (4, 2.1 Gayu), 7.80 (y, 2H, 1-71

Go), 7.66 (8, 2H, 7: 9 Ha), 7.10 (b5, IN); 1927 NMR (SOSIZ): -17682 apa -44362;

PH/MS: purity: 9195 apa M5 (mass/charge) in: 292 (MN.V). « hall 2-chloro-M4-(4-chloro-3- Analogously to the preparation of 2-chloro-5-fluoro-M4-I3-(1H-tetrazo-5-yl)phenyl|-4-trifluoromethylphenyl)-5-fluoro -4-pyrimidinamine, 2-chloro-M4-4(4-chloro-3-trifluoromethylphenyl)-5-fluoro-4- pyrimidinamine (К926877) pyrimidineamine is restrained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine with 4- with chloro-3-trifluoromethicaniline. 1H NMR (CITY): 5 8.15 (4, IN, 15 2.1. Hn), 7.96 (4,

IN, 7-3 Gy), 7.91 (49, IN, 12.7 Hz and 8.7 Gy), 7.53 (6, 1H, 3-8.1 Gy), 7.06 (B5, 1NU ; ; with 19KE NMR (SOSIZ): -17892 apa -44402; LC/MS: purity: 9399; MS (mass/charge); 326 (MU. 7.1.75 2-chloro-5-fluoro-M4-(6- methoxypyridine-3- | Analogously to the preparation of 2-chloro-5-fluoro-M4-|3-(1 H-tetrazol-5-yl)phenyl|-4- yl)-4-pyrimidinamine (KO25878) pyrimidineamine, 2-chloro- 5-fluoro-M4-(6-methoxypyridine»3-y|)-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-amino-b-(ee)methoxypyridine. TN NMR (SOZOB) : 6 8.39 (4, 1H, 7- 3.0 Hz), 8.10 (4, 18, - 3.6

Gi), 7.95 (49, EN, 3» 2,4 and 9 Hn), 8.30 (y, 1H, 1-9 Gv), 3.91 (5, ZN); 19E NMR km (СО3О0): -44737; VK/MS: purity: 9795; MS (mass/charge): 255 (Mn). 74.76 2-chloro-M4-(3,4-difluorophenyl)-5-fluoro-4- | Analogously to the preparation of 2-chloro-5-fluoro-MA-| 3-41 H-tetrazol-5-yl)phenyl|-4- - PD Shyny t on z « A «o 6 20 OS lo (Se) 42) ko 60 b5 pyrimidineamine (K926882) pyrimidoquinamine, 2-chloro-M4- (3,4-difluorophenyl)-5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine with 3,4-difluoroaniline. IN NMR (SOSIZU: 5 8.10 (4, 1H, 1-2, Gi), 7.72 (t, 1 NU, 7.22 (t, 2NI), 6.95 (b, 1H); РХ/ MS: purity: 9395; MS (mass/charge): 260 (MU 741.77 2-chloro-M4-(3,4-dichlorophenyl)-5-fluoro-4- | Similar to the preparation of 2-chloro-5-Ffluoro-M4- I3-441H-tetrazol-5-ylphenyl|-4- pyrnmidinamine (2926884) pyrimidineamine, 2-chloro-144-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidinamine are obtained as a result of the reaction of 2,4-dichloro - of 5-fluoropyrimidine with 3,4-dichloroaniline. LC/MS: purity: 9595; MS (mass/charge): 294 (M. 2B). 71.78 2-chloro-5-fluoro-M4-(6-methylpyridine-2-) Analogously to preparation 2-chloro-5-fluoro-M4-13-01H-tetrazol-5-yl)phenyl|-4-yl)-4-pyrimidinamine (К926888) pyrimidineamine, 2-chloro-5-fluoro-IR4-(b-methypyridine -2-yl)-4-pyrimidinamine is obtained as a result of the reaction of 2,4-polychloro-5-fluoropyrimidine with 2-amine-b-methylpyridine. 1H NMR (SUSIII): δ 8.23 (5, 1H), 8.19 (5, 1H ), 8.12 (y, 1H, 253

Ho), 7.55 (B5, EN), 7.69 (b IN, 1-7.4 Gy), 9.35 (4, 1H, 15: 7.5 Hn); 19E NMR (SOSIZ); -44073; LC/MS: purity: 9695; MS (masg/charge): 239 (M). 7.1.79 2-chloro-Ma-(2,6-dimethoxypyridin-3-yl)- Analogous to the preparation of 2-chloro-5-fluoro-m4-(3-(1H-tetrazol-5-yl)phenyl-4- 5 -fluoro-4-pyrimidicamine (K926889) of pyrimidine, 2-chloro-M4-(2,6-dimethoxypyridine-3-1l)-5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 7,4-dichloro-5-fluoropyrimidine with 3-amine-2,6-dimethoxypyridine. 1H NMR (SRS): δ 8.57 (4, IN, 2: 8.7 Gy), 8.02 (d, 1H, 1-27

Hz), 6.40 (Y, 1H, /- 8.1 Gy), 4.03 (5, ZM), 3.98 (z, ZN); 19E YAM (SOSIZ): -44640;

LC/MS: purity: 9095; MS (mass/charge) in: 285 (MU). 7.1,80 2-chloro-M4-(6-chloropyridine-3-1l)-5- Similar to the preparation of 2-chloro-5-fluoro-Ma-13-(1H-tetrazol-5-yl)phenyl|-4- fluoro -4-pyrimilinamine (K920400) pyrimidineamine, 2-chloro-M4-(6b-chloropyridin-3-yl)-5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-amine- 5- chloropyridine. IN NMR (SOSIS): g 8.53 (0, 1H, 7-3 Hz), 8.25 (94, 1H, 1-Z and9

Hz), 8.15 (4, IN, 72 2.4 Hz), 7.39 (Ф 1, 1e 8.7 GK sh), 7.00 (65, IN); LC/MS: purity: 9895; MS (mass/charge) in: 259 (Mk). 74.81 2-chloro-5-fluoro-M44(4-methylpyridin-2- similar to the preparation of 2-chloro-5-fluoro-M4-1341H-tetrazol-5-yl)phenyl-4"yl)-4-pyrimidinamine (K920401) of pyrimidine, 2-chloro-5-fluoro-YH4-(4-methylpyridin-2-yl)-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine with 2-amino-4-methylpyridine. IN NMR (SOSIZ): 018.22 (5, 1H), 8.16 (4, 1H, 1-8.4 Gy), 8.13 (4, 1TH, 1-2.4 Hz), 6.91 (y, IN, )- 5.4 GB), 2.42 (5, ZN); LC/MS: purity: 875; MS (mass/charge) in: 239 "MN. 17182 2-chloro-5-fluoro-M4-(3- Similar to the preparation of 2-chloro-5-fluoro-M4-I34(1H-tetrazol-5-yl)phenyl|-4- trifluoromethoxyphenyl)-4-pyrimidinamine | of pyrimidine, 2-chloro-5-fluoro-YM4-(3-trifluoromethoxyphenyl)-4-pyrimidinamine (K920402) is obtained as a result of the reaction of 2,4-lichloro-5-fluoropyrimidine with 3-trifluoromethoxyaniline. IN NMR (SOSIS): 11 8.12 (0, 1H, 1: 3 Hz), 7.68 (65, 1), 7.53 (49, 1H, 1-: 1.2 and 8.4 Hz) , 7.41 9, 1H, 12 8.1 Gi, 7.04 (bd 2H); 197 YAMER (SOSIZ): -16430 and -44463; LC/MS: purity: 8995; MS (mass/charge): 308 (MINES). 7.1.83 2-htyur-MA34- Similar to the preparation of 2-chloro-5-fluoro-M4-13-1H-tetrazol-5-yl)phenyl|-4-(Ce)difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine . IN NMR (SOSIS): I7 8.09 (4, EN, U: 3 Gy), 7.79 (6, 1H, 1-24 Ho) 7.10 (49, IN, 1-24 and 8.7 Gy ), 7.06 (I, IN, 7-2 8, G i), 6.97 (B5, 18; 192 NMR (SOSIZ): "14175 and -44562; LC/MS: purity: 9596; MS (mass /charge): 304 h (M.N. 71.84 2-chloro-5-fluoro-M4-(quinolin-b-yl)-4- Analogous to the preparation of 2-chloro-5-fluoro-M4-(341H-tetrazol-5-yl )phenyl|-4- with pyrimidineamine (8920409) pyrimidineamine, 2-chloro-5-fluoro-M4-(quinolin-b-yl)-4-pyrimidinamine is obtained in

From the reaction of 2,4-dichloro-5-pyrimidine with b-aminoquinoline. IN NMR (ge) ("SOSISu: 2 8.02 (yd, 1H, /- 2.7 Hz), 8.09 (ad, 1H, 1-5 2.4 Gy), 7.734, IN, 159 Gy) , 7.68 (ai, IN, 1-24 and 8.7 Gy), 7.28 (y, IN, 1- 10.5 Hz), 6.42 (y, IN, 1- 9.3 Gy) ; 19E

NMR (SOSISU -44344; LC/LMS: purity: 9195; MS (mass/charge): 292 (M.N). 7.1.85 2-chloro-M443-yuur-4- Similar to the preparation of 2-chloro-5-fluoro -M4-|34 1 M-tetrazole-5-1l)phenyl|-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidinamine, 2-chloro-M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro- 4- « pyrimidineamine pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-chloro-4-trifluoromethoxyaniline. 1H NMR (SOSIS); P 8.15 (4, 19, 1- 3.0 Gy), 7.86 shsh (4.1H,- 2.1 C), 7.61 (46, IN, 2- 2.1 and 8.7 Co), 7.354, 1H, 32 1.2 and 8.7 Hn), 6.95 s (rb5, 1H); LC/MS: purity: 97; MS (mass/charge): 342 (Ma2H). n » 7.1.86 2-chloro-M4-(4-chloro-3-methoxyphenyl)-5- Similar to the preparation of 2-chloro-5-fluoro-M4-13-44I1 H-tetrazol-5-yl)phenyl-4- and fluoro-4-pyrimidinamine of pyrimidine, 2-chloro-M4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-aminopyrimidine are obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-chloro-3 - methoxyaniline. LC/MS: purity: 8895; MS (mass/charge): 288 (MNK). 741.87 d-chloro-5-fluoro-m4-124(2- Analogously to the preparation of 2-chloro-5-fluoro-M4-13411H-tetrazol-5-iluphenyl-4-(se) hydroxyethyleneoxy)pyridin-5-yl|-4 - pyrimidine, 2-chloro-5-fluoro-M4-(2-(2-hydroxyethyleneoxy)pyridin-5-yl|-4-pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine with 5-amine- 2-(2-hydroxyethyloxy)pyridine. IN NMR (SUS): 0 8.28 (0, 1H, 2-24 Hu, co 8.08 (t, 1), 7.99 (t, 1), 7, 00 (B5, I NU, 6.87 (54, IN), 4.47 (t, 2H), 3.97 (tz, 2H). - 7.1.88 2-chloro-M4-124 (2-chloro- 5-fluoropyrimidine- | Analogously to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-4-yl)-1,2,3,4-hetrahydroisoquinolin-7-yl|-pyrimidinediamine, 2- chlorine-M4-(2-(2-chloro-5-fluoropyrimidine-4-1l)-1,2,3,4- (Ce) 42) ko 60 b5

5-fluoro-4-pyrimidinamine (5926910) tetrahydroisoquinoline-7-1l)-5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-3-fluoropyrimidine and 7-amine-1,2,3,4- tetrahydroisoquinoline. IN NMR (SOSIZuU 8.08 (0.1, 2-5 3.0). 7.95 (0.1, le 6.0 Hz), 7.50-7.42 (t, 2), 7, 21 (9, 1H, /: 8.4 Hz), 6.96-6.90 (t, 1), 4.95 (5, 2H), 4.04 (6, 2H, 22: 5.7 Hz ), 2.99 (6 2H, 12 5.7 Hz); 19E NMR (282 MHz, SOSISU; -42555, -44573; LC/MS: purity: 9890; MS (mass/charge): ZD (MN). 7.1,89 2-chloro-5-fluoro-ma-(2-(- Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-butoxycarbonyl).1,2,3,4 - tyrimidine, 2-chloro-5-fluoro-M4-|2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl|-4-tetrahydroisoquinolin-7-yl|-4-pyrimidinamine are obtained as a result of the reaction of 2,4-pyrimidinamine (5926911) of dichloro-5-fluoropyrimidine and 7-amino-2-(t-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline. IN NMR (SRSISU О 8.03 (5, 1), 7.50-7.26 (t, 2H), 7.19-7.11 (t, 2H), 4.57 (5, 2NU, 3.64 (I, 2H, 12 5.7 Hz ), 2.80 (6 2H, 1-5.7 Gy), 1.48 (5, 9NU;

LC/MS: purity: 8995; MS (mass/charge): 37 M). 7.1.90 2-chloro-5-fluoro-M4-(1,2,3,4- Solution of 2-chloro-5-fluoro-M4-(2-(t-butoxycarbonyl). I,2,3,4- tetrahydroisoquinolin-7-tetrahydroisoquinolin-7-yl)-4-yl|-4-pyrimidinamine in 4095 trifluoroacetic acid and dichloromethane pyrimidineamine (K926912) is stirred at room temperature for 30 minutes. After removing the solvent, an oily precipitate is obtained, which is suspended in water, made basic with ManSOZ and liberated with ethyl acetate. IN NMR 715 (SOSISU: P 8.04 (4, 1H, 7- 3.0 Hn), 7.37 (40, 1H, 7: 2.4 and 8.4 g), 7.27 (0, 1Н.2-1.5 гу and NI -8.4 Hz), 6.92 (5, 18), 4.04 (5, 2Н), 3.15 (6 2Н, 1- 6.0 Hz ), 2.79 (6 2H,. 1- 6.0 Hz); 19E NMR (282 MGy, SOSIS): -44648; LC/MS: purity: 9795; MS (mass/charge): 779 (MH B) . and 2-chloro-3-fluoro-M4-(4-methyl-3- Analogously to the preparation of 2-chloro-Ma-(3,4-ethylenedioxyphenyl)-5-fluoro-4-trifluoromethylphenyl)--pyrim idynamine of pyrimidine, 2-chloro-5-fluoro-144-(4-methyl-3-trifluoromethylphenyl)-4-41К926920) pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-20 methyl-3-trifluoromethylaniline . IN NMR(SOSTI) U: 8.10 (a, 1, 7: 3.0 h), 7.85-7.78 (t,2NUu 7.33 (y,1H, /- 9.3 Hz), 6.96 (b5, 1H), 2.48 (b, ZN, I 1.2 Gy); 192 NMR (282 MHz, SOSIZ): "17641, -44541; LC/MS: purity: 9795; MS (mass /charge): zО06b(Mn-). 7.1.92 2-chloro-5-fluoro-M4-(4-fluoro-3- Analogous to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro- 4-methylphenyl)-4-pyrimilinamine (926921) | pyrimidineamine, 2-chloro-5-fluoro-M4-(4-fluoro-3-methylphenyl)-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-fluoro-3-sem 25 methylaniline. IN NMR (SOSISU: (1 8.06 (y, IN, 3- 2.4 Hz), 7.48-7.43 (t, 19, 7.39 ( 44, N.I 2.7 and 6.3 Gy), 7.03 (K, IN, 15:90 Hyd), 6.84 (08, 1H)), 2.304, 1H, 12 1.8 o

Hz); I9E NMR (282 MHz, SOSIZ): -34285, -44676; LC/MS: purity: 9595; MS (mass/charge): 23'MNU. 7.1.93 744-134 ((M-th) Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-butoxycarbonyl)aminemethyl-4-pyrimidinamine, M4-Y3-Y(M-th -butoxycarbonyl)aminemethyl|-4-methylphenyl|-2-chloro-5-(Che)methylphenyl|-2-chloro-5-fluoro-4-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5- 30 pyrimidineamine (K926924) fluoropyrimidine and 3-|(M-t-butoxycarboni l)aminemethyl|-4-methylaniline. IN NMR b (SUOSHIZ): 0 8.05 (d, IN, /- 3.0 Hz), 7 .52 (y, IN, 3- 9.3 Gy), 7.45 (5, 1H), 7.19 (4, IN, 12 8.1 Hz), 6.96-6.89 (t, 1H ), 4.80 (be, 1H), 2.31 (5, 2H)), 1.46 (c, 9H); LC/MS: purity: 9705; MS (mass/charge): 311 (M - (i-butyl) 5). h- 7.3.94 2-chloro-М4-3-Ц4- Analogously to the preparation of 2-chloro-М4-(3,4-ethylenedioxyphenyl)-5-fluoro-4- (ethoxyaerbonyluliperidino|methyl|phenyl|pyrimilinamine, 2-chloro- ма4-(34(4-(ethoxycarbonyl)piperidino|methyl|phenyl|-5-s 1-5-fluoro-4-pyrimidinamine fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-3B fluoropyrimidine and ethyl -(Z-aminobenzyl)piperidine-4-carboxylate. LC/MS: so purity: 9795; MS (mass/charge: 3394MH). 7.195 2-chloro-M443-(4- Analogously to the preparation of 2-chloro-M4-(3 . aniline reacts to form 2-chloro"pyrimidinamine m4-13-(4-(ethoxycarbon)piperilino|carbonyl|phenyl|-5-fluoro-4-pyrimidinamine, "

LC/MS: purity: 9695; MS (mass/charge): 407(M Z). 40 7.1.96 2-chloro-5-fluoro-M4-4(1,2,3,4-tetrahydro-1- | Similar to the preparation of M4-(3,4-ethylenedioxy)-5-fluoro-M2-(2- (hydroxymethyl)benzofuran-5-171-2,4-pyrimidinediamine, 2-chloro-5-fluoro-M4-(1,2,3,4-s tetrahydro-1 -oxonaphthalen-7-yl)-4-pyrimidinamine is reduced with diisobutylaluminum hydride (Biba!-H) in order to form 2-chloro-5-fluoro-M4-z" (1,2,3,4-tetrahydro-I- hydroxynaphthalene-7-yl)-4-pyrimidinamine. 1H NMR (SOSIS): k n 8.05 (0, YIN 2- 3.0 Hz), 7.59 (0, 1H, 1-2 2.4 Gy) , 7.14 (4, 1, 12 8.1 Go), 6.93 (B5,

IN), 4.82-4.78 (t, 1H), 2.82-2.71 (t, 2), 2.08-1.74 (t, 5H); 192 NMR (282 MHz,

SOSIZ) -44661; LC/MS: purity: 9495; MS (mass/mass): 294(MN). 71.97 dechloro-5-fluoro-M4-(1,2,3,4-tetrahydro-1- | Similar to the preparation of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-(ee) oxonaphthalene- 7-yl)-4-pyrimidinamine, pyrimidinamine, 2-chloro-5-fluoro-M4-(1,2,3,4-tetrahydro-1-oxonaphthalene-7-yl)-4-pyrimidinamine are obtained as a result of reaction 2, 4-dichloro-5-fluoropyrimidine and 7-ko amine-I-stralone. 1H NMR (PM50-46): :: 10.08 (5, 1, 8.31 (4, 1H, 7: 3.3 Gy), 8.15 (4.1H, 3-24 Hz), 7.82 ( 09, 1H, 1: 2.4 and 8.1 Hz), 7.36 (y, IN, 7/- 8.1 Gy), 2.91 (, 2H, 1-6.0 Gy), 2, 59 (0 2H, 15 6.0 Hz), 2.07-1.98 (t, 2H); LC/MS: purity: 9395; MS - (mass/charge); 2944MNY. (Se) 42) ko 60 b5

7.1.98 2-chloro-5-fluoro-M4-Y3- Similar to the preparation of 2-chloro-IM4-(3,4-ethylenedioxyphenyl)-3-Fluoro-4-(trifluoromethylthiophenyl|-4-pyrimidinamine, 2-chloro-5 -fluoro-Ma-(3-(trifluoromethylthiophenyl)-4-pyrimidinamine pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-(trifluoromethylthio)aniline. 1H YAMA (SOSIZ): 7 8.13 (65, 10), 7.92 (B5, 1, 7.89-7.84 (t, 1H), 7.48-7.45 (t, 2H), 7.04 (05, 1H); LC/MS: purity: 9796; MS (mass/charge: 325IMN) 7.1.99 2-chloro-5-fluoro-M4A-(3- Similar to the preparation of 2-chloro-IM4-(3,4-ethylenedioxyphenyl)-5-fluoro-4 - dihydroxyboryl)phenyl)|-4-pyrimidinamine, 2-chloro-5-fluoro-M4-|(3-dihydroxyboryl)phenyl))-4-pyrimidinamine pyrimylinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3 - aminebenzeneboronic acid. 741100 2-chloro-5-fluoro-M4-KI1H)-indol-b-yl|-4- Similar to the preparation of 2-chloro-144-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, 2- chloro-5-fluoro-m4-C1H)-indoia-6-yl|-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and b-aminoindole. PH/MS: purity: 925; MS (mass/charge): 263(MIN-). 741191 2-chloro-5-fluoro-Ich4-(2-hydroxy-4- Analogous to the preparation of 2-chloro-Ich4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-methylphenyl)-4-pyrimidinamine pyrimidinamine, 2- chloro-5-fluoro-M4-(2-hydroxy-4-methylphenyl)-4-pyrimidicamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methylaniline. LC/MS: purity: 9750; MS (mass/charge: 255IMN). 7.41.102 2-chloro-5-fluoro-M4-H2-4(methoxycarbonyl)- | Similarly to the preparation of 2-chloro-Ma-(3 4"ethylenedioxyphenyl)-5-fluoro"d" (IN) indole-b-yl|-4-pyrimidinamine pyrimidineamine, the reaction of 2,4-dichloro-5-fluorotrimyline with b- change-2" (methoxycarbonyl)-(1H)-indole to form 2-chloro-5-fluoro-m4-(2-(methoxycarbonyl)"(1H)-indol-6-ylI-4-pyrimidinamine, which was used without further purification. LC/MS: purity: 6595; MS (mass/mass); Z2YMN U. 71.93 Mma4-|344-(2-chloro-5-fluoropyrimidine)-M- Reactor with magnetic stirrer and rubber membrane (with in order to prevent the loss of aminemethylene)-phenyl|-2-chloro-5-fluoro-4- 2,4-dichloro-5-fluoropyrimiline) and the hole for the introduction of MO is filled with 3-pyrimidinamine (К940298) aminebenzylamine (0.22 g, 1.79 mmol ), MeOH (1 mL), H2O (3 mL), and 2,4-dichloro-5-fluoropyrimidine (0.3 g, 1.79 mmol). The reaction mixture is stirred at 800C for 30 minutes, cooled to room temperature and washed with water. (30 ml). After saturation with sodium chloride, the mixture is extracted with ethyl acetate (3 x 20 ml), dried over anhydrous sodium sulfate, and the solvent is removed. The resulting residue is filtered through a silica gel pad (200-400 mesh - number of cells per linear inch - translator) using 1 to 395 MeOH in CH2Cl2 to form se 7a-(3-64-(2-chloro-5-fluoropyrimidine) )-M-methylaminemethylene)-phenyl|-2-chloro-5-fluoro-4-pyrimidinamine (8940298). IN NMR (OM5O-c6): - 10.09 (1H, 5), 8.88 (IN. 6712 at 5.85 Gy), 85.40 (1H, 4, 1- 3.6 Hz), 8, 23 (IN, 4, 2 3.3 Hz), 7.74 (IN, 5), 7.70 Х1Н, а, 3- 81 Hz), 7.44 (1Н, 5 1-7.8 Hz), 719 (IN, y, 22 8.1 Gy), 4.69 (2Н, 4, 2- 5.7 Hz; purity 92 95. zt4lo4 2-chloro-5-fluoro-M4-3- Reactor with a magnetic stirrer and with a rubber membrane (in order to prevent methyloxycarbonyl-4-methoxyphenyl)-4- loss of 2,4-dichloro-5-fluoropyrimidic) and the hole for the introduction of M2 is filled with 3-(se)pyrimidinamine (K940302) methyloxycarbonyl-4-methoxyanilic (0.88 g, 4.86 mmol), MEON (3 mL), HgO (7 mL), and 2,4-dichloro-5-fluoropyrimidine (0.81 g, 4.86 mmol). The reaction mixture b) is stirred at 600°C for 30 minutes, dissolved in water (50 ml), acidified with a 2M NOI solution (6 ml) and dispersed using ultrasound.

The obtained solid fraction is filtered, washed with water and dried in order to obtain 2-chloro-5-fluoro-ma-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidinamine (K940302). IN NMR. (0М50-а6): 110.19 (1H, 5), 8.39 (IN, d, 1- sem 3.6 Ha), 804 IN, d, 1-27 i), 7.98-7.93 (1Н, т), 7.30 IN, 9, 3- 9 Hz), 3.92 (ЗН, 5), 3.89 (ЗН, т); purity 9695 ; MS (mass/charge): 312 (MNK). c z4Ll05 2-chloro-5-fluoro-M4-(4-phthalimide)-4- Analogous to the preparation of 2-chloro-5-fluoro-M4-(3-methyloxycarbonyl-4-pyrimidinamine (K940303) methoxyphenyl)-4-pyrimidicamine, 2-chloro-5-fluoro-MA-(4-phthalimide)-4-pyrimidinamine (8940303) is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-aminophthalimide. IN NMR. (0ОМ5О-4й6): 1 11.38 (IN, 5), 10.60 (IN, 5), 8.57 (1Н, 4, и- 3.3 Gy), 8.39 (1 Н, и, 72 1.8 GI), 8.181 N, y, 12 8.4 Hz, 1-2 2 C), 7.93 (IN, 6, U- 8.1 "

Hz); purity 9095 ; MS (mass/charge): 293 (MIC). 741106 2-chloro-5-fluoro-M4-4(3- Similar to the preparation of 2-chloro-5-fluoro-M4-(3-methyloxycarbonyl-4.2 methypaminecarbonyl-4-methoxyphenyl)-4- methoxyphenyl)-4-pyrimidinamine . -4-methoxyaniline, IN YAMI n » (0РМ5О-а6): DC 9.91 (1Н, 53, 8.31 KHAN, 4, 2-5 3.6 Го), 8.11 НН, а, 3-2.7 Hz), 7.78 (1H, i aa, 2-59 gy, -2.7 Hz), 7.59 PIN, t), 6.87 (IN, f, 359 Gy), 3.90 (ZN, 5) , 2.96 (ZH, y, y- 4.5 Hz); purity 9395. 7.41.107 1M2-chloro-5-fluoro-Ма4-|3-(М- Similar to the preparation of 2-chloro-5-fluoro-М4-(3-methyloxycarbonyl-4- morpholinemethylene)-4-methoxyphenyl-4- methoxyphenyl)-4-pyrimidinamine, 2-chloro-5-fluoro-M4-I3-(M-morpholinmethylene)-4-pyrimidinamine (К940313) methoxyphenyl-4-pyrimidinamine (2940313) are obtained as a result of the reaction of 2,4-dichloro- of 5-fluoropyrimidine and 3-(M-morpholinemethylene)-4-methoxyaniline. IN NMR (OM50-46): 210.00 (1H, 5), 8.35 (1H, d, 1-3.3 Hz), 7.72 (1H, d, 4-3 Hz), 7.58 (IN, where 9.3), 7.2 (IN, a, 1-8.4 Gy), 3.89 (Z, 5), 3.8-3.5 (OH, t), 2 .58 (4H, t); purity 9695 ; MS (mass/charge): 352 (M). Similar to the preparation of 2-chloro-5-fluoro-M4-(3-methyloxycarbonyl-4-

RE

(Ce) 42) ko 60 b5 methclaminemethylene)-phenyl|-2-chloro-5-methoxyphenyl)-4-pyrimidinamine, M4-|34(M-tert-butoxycarbonyl-M-fluoro-4-pyrimidinamine (KO40315) methylaminemethylene) -phenyl)-2-chloro-5-fluoro-4-pyrimidinamine (8940315) is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-(M-tert-butoxycarbonyl-M-methylaminemethylene)aniline. IN NMR (0M50-46): SI 10.131Н, 5), 8.42 (1Н, d, 72 3.6 Hn), 7.69 (IN, t), 7.64 (1Н, 5), 7, 45 (1H, , 32: 7.6 Hz), 7.09 (IN, y, 7-: 7.8 Hz), 448

СН, 5), 2.90 (ЗН, 5), 1.49 (9Н, т); purity 9225; MC (mass/charge): 367 (MN). 741409 Ma43-(M-tert-butoxycarbonyl-M-iso- Analogously to the preparation of 2-chloro-5-fluoro-Ma-(3-methyloxycarbonyl-4-propylaminemethylene)-4-methoxyphenyl)-2- | methoxyphenyl)-4-pyrimidinamine, M4-(3-(M-tert-butoxycarbonyl-M-iso-chloro-5-fluoro-4-pyrimidinamine (K940320) | propylaminemethylene)-4-methoxyphenyl)-2-chloro-5- fluoro-4-pyrimidinamine (2940320) is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-0M-tert-butoxycarbonyl-M-iso-propylaminemethylene)-4-methoxy-aniline. IN YAME (PM5Odv): С 10.01 (IN, 5), 8.34 (1 d, 1: 3.6 Gy), 7.52 (2Н, tu, 7.08 (IN, df, 3 - 8.7 Hn), 4.33 (ZH, t), 3.90 (ZH, 5), 1.50-1.30 (9H, pa), 1.18 (6H, 4.31 6.9 Purity 9595. 7.1.110 2-chloro-Х4-|((2,2-dimethyl-4H- Analogous to the preparation of 2-chloro-5-fluoro-M4-(3-methyloxycarbonyl-4- benzo 1,4oxazine- 3-one)-6-yl)-5-fluoro-4-methoxyphenyl)-4-pyrimidinamine, 2-chloro-M4-((2,2-limethyl-4H-benzoyl)oxazine-3-pyrimidinamine (K940322) )-b-yl|-5-fluoro-4-pyrimilinamine (K940322) is obtained as a result of the reaction of 2,4.dichloro-5-fluoropyrimidine and the compound b-amine-2,2-dimethyl-4H-benzoin 1 ,4 |oxazin-3-one. IN NMR. (0M5O-46): P 10.89 (1H, 5). 10.04 (IN, 8). 8.38 (1H, y, /- 3.6 7.35

OH, t), 7.04 (1H, d, 1-8.4 Gy), 1.506H, 5); purity 91.496; MS (mass/charge: 322 75 (M). 741111 2-chloro-M4-|3»-dihydro-2,2-dimethyl-4-/2- Analogous to the preparation of 2-chloro-3-fluoro-Ma-(3 -methyloxycarbonyl-4-"(tridyl-1-oxydi-benzo|1,4 oxazine-b-methoxyphenyl)-4-pyrimidinamine, 2-chloro-M4-|3-dihydro-2,2-dimethyl-4-(2 -(pyridyl-yl|-5-fluoro-4-pyrimidinamine (5940328) 1-oxide)-benzo 1,2oxazin-b-ylI-5-fluoro-4-pyrimidinamine (K940328) is obtained as a result of the reaction of 2,4-dichloro -5-fluoropyrimidine and 2-(6-amino-3-dihydro-2,2-dimethyl-benzo|1,4|oxazin-4-yl)pyridine 1-oxide. IN NMR (0M50-y46): C 9, 82 (IN, 5), 8.39 (1H, aa, 6.3 Hz, 2 Hz), 8.30 (IN, y, 3.6 Hz), 7.63 (IN, aa, 3: 8, 4 Gu,

Te24 Hz) 747 (On, 7.5 Hz, 158 Hz), 7.34, tu, 7.21 (IN, yes, I 8.7 Hz, other 24 Sv, 707 (N.Y 2.7 Ha) , 6.91 1.3 8.7 Gy), 3.64 (2H, 5), 1.41 (6H, 5); purity 95.895; MS (mass/charge): 402 (MN.Yu. 741.12 2-chloro-m4-(3-dihydro-2,2-dimethyl-4-(2-) Analogously to the preparation of 2-chloro-5-fluoro-M4-(3 -methyloxycarbonia-4-pyridyl)-benzo| and, Hoxazin-6-ylI-5-fluoro- | methoxyphenyl)-4-pyrimidinamine, 2-chloro-M4-|3-dihydro-2,2-dimethyl-4-( 2-pyridyl)-4-pyrimidinamine (К940336) benzo 1,4 |oxazin-b-yl)-5-fluoro-4-pyrimidinamine (5940336) is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and b-amine -Z-dihydro-2,2-dimethyl-4-(2-pyridyl)-benzo|1,4)oxazine. IN NMR (0M5O-v6): C 9.95 (IN, 5), 8.38 (1H, ad, with 4.8 Ho, 1.8 Gy), 8.33 (1H, a, 7 3 ,6 Go), 7.84 (IN, 0, 12 2.1 Gy), 7.79 (IN, give, 7 o 15.6 Hz, 7.2 Hz, 2.1 Gy), 7.57( H, a, etc. 8.4 g), 7.19, ad, 7- 8.4 Hz, 3- 2.4 Hz), 7.01-6.95 (2H, t), 3.96 (2H , 5), 1.32 (6H, 5); purity 99.392; MC (mass/charge): 386 (MN). 7.1l13 2-chloro-Ma-|(2,2-difluoro-4H- Analogously to the preparation of 2-chloro-5-fluoro-M4-(3-methyloxycarbonyl-y-benzo I, 4oxazin-3-one)-b-yl |-5-fluoro-4- methoxyphenyl)-4-npyrimidinamine, 2-chloro-M4-1(2.2-difluoro-4H-benzo| 1,4 |oxazin-3- (se) pyrimidineamine (K940342) on)-b -yl|-5-fluoro-4-pyrimidinamine (2940342) is obtained as a result of the reaction of 2,4-lichloro-5-fluoropyrimiline and the compound 6-amine-2,2-difluoro-4H-benzo 1, oxazine-3- (e ») Mr. IN NMR (0M50-a6): (112.24 (1H, 85U, 10.23 (1H, 5), 8.45 (IN, ai, 1-2 3.3 Hz, 1- 0.9 Hz), 7.661N, aa, le 42 Hn, 7-24 Hz), 7.55 (IN, and 12 9 Hz, their 2.5 Hz), 7.43 "- (IN, a and 9 Hz; 19E NMR (0М50 -46); 0 -21582, -43415; purity 96.2, MS (mass/charge): 331 (MH). ch 7.1.414 2-chloro-M4-((2,2-dimethyl-4H-5- Similarly to the preparation of 2-chloro-5-fluoro-M4-(3-methyloxycarbonyl-4-pyrido 1,oxazin-3-one)-7-yl-5-fluoro-4- | methoxyphenyl)-4-pyrimidinamine, 2-chloro -M4-Y((2,2-dimethyl-PH-5-so pyrimidineamine (К940344) pyrido|1,oxazin-3-one)-7-1l|-5-fluoro-4-pyrimidinamine (К940344) is obtained as a result of the reaction 2,4-pichloro-5-fluoropyrimidine and the compound 7-amino-2,2-dimethyl-4H,5-pyrido I,4oxazin-3-one. IN NMR (BM5O-46): 11.32 (1, 5) , 10.20 (1H, 8), 8.45 (IN, a, 2- 3.6 Gy), 8.33 (IN, 4, 3-2, Snu, 7.84 (IN, y, 1- 2 SOU, 1.54 (6H, 8); purity 90.895; MS (mass/charge): 3724 (MH). 74115 Mma-(4-aminocarbonylmethyleneoxyphenyl)- | Similar to the preparation of 2-chloro-M4-(3,4- stylenedioxyphenyl)-5-fluoro-4-" 2-chloro-5-fluoro-4-pyrimidinamine p irimidinamics, M4-(4-aminocarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4- (8945028) pyrimydicamine is restrained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine (250 mg, 1.50 mmol) and 4 -aminocarbonylmethyleneoxyaniline (540 mg, 3.25 mmol).

LC/MS: retention time: 18.34 minutes; purity: 10095; MS (mass/charge): "from 298.47 (MNU. k 7.41.116 2-chloro-5-fluoro-MA-T2H-pyridoy 3,2-51- Analogous to the preparation of 2-chloro-m4-(3,4-ethylenedioxyphenyl )-5-fluoro-4- 1,4-oxazin-X4H)-ovn-6-yl|-4-pyrimidinamine, 2-chloro-5-fluoro-M4-|(2H-pyridoy 3,2-5|- 1,4-oxazin-3(4NI)-one-6-yl)|-4-pyrimidinamine (K945298) pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and the compound b-amino-2H-pyrido| 3 ,2-51-1,4-oxazin-3(4H)-one 18 NMR (0M50-46u: 0 o 4.63 (5, 2), 7.34 (4.43- 8.7 Hz, IN ), 7.44 (0.22: 8.4 Hz, 1H), 8.33 (4, 1- 3.3 Gy, 189, 10.14 45, 1H, MH), 11.19 (5, IN , MH); 19E NMR (282 MHz, OM50-46): 1 -152.35;

LC/MS: retention time: 26.74 minutes; purity: 85.90; MS (mass/charge): ko 296.3 (MH. - Analogously to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-fluoropyrimidinamine pyrimidineamine, M4A-(1,4-benzoxazine-b -yl)-M2-chloro-5-fluoropyrimidinaminium is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and b-amino-1,4-(Ce) (42) with 60 b5 benzoxazine. IN OM5O 8.2 ( y, 1H),6.8 (t, 1H), 6.75 (t, IN), 6.60 (t, 1), 4.05 (t, 2H), 3.2 (pu, 2NI) purity 95 25 MS (mass/charge): 28 (МН. 71.18 М441,4benzoxazine-7-11) |-М2-chloro-5- Similar to the preparation of 2-chloro-М4-(3,4-ethylenedioxyphenyl)-5-fluoro- 4-fluoropyrimidinamine of pyrimidine, M4-(1,4-benzoxazin-7-yl)|M2-chloro-5-fluoropyrimidinamine is obtained as a result of the reaction of 2,4-lichloro-5-fluoropyrimidine and 7-amino-1,4-benzoxazine. INOM5O 8.2 (4, 1H), 6.8 (t, 18), 6.75 (t, IN), 6.60 (t, 1H), 4.05 (t, 2H), 3.2 ( t, 2NI) purity 94 95 MS (mass/charge): 28 (MH). 7419 M4-(1,4-benzoxazin-3-on-6-yl)-M2-chloro- | Similar to the preparation of 2-chloro-M4 -(3,4-ethylenedioxyphenyl)-5-fluoro-4-5-fluoropyrimidinamine, M4-(01,4-b) enzoxazin-3-one-b-yl)-M2-chloro-5-fluoropyrimidicamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and the compound 6b-amino-1,4-benzoxazin-3-one. IN ЮМ5О 8.2 (4, 1), 6.8 (t, IN), 6.75 (t, 1Н), 6.60 (t, 1Н), 70 4.73 (5, 2Н) purity 96 55 MC (mass/charge): 295 (MN). 71120 M4-(1,4-benzoxazin-3-one-7-yl)-M2-chloro- | Similar to the preparation of 2-chloro-Ma4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-5-fluoropyrimidinamine pyrimidineamine, M4-(1,2-benzoxazin-3-on-7-yl)-M2-chloro-5 -fluoropyrimidinamine is obtained as a result! reactions of 2,4-dichloro-5-fluoropyrimidine and the compound 7-amino-1,4-benzoxazin-3-one. TYA RM5BO 8.2 (y, 1H), 6.8 (t, 1H), 6.79 (t, IN), 6.6 (n 1H), 4.68 (5, 2H) purity 93 95 MS ( mass/charge): 295 (MN). 74421 M2-chloro-5-fluoro-M4-(M-methyl-1,4- Similar to the preparation of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-benzoxazin-b-yl)-pyrimidinamine pyrimidineamine, M2-chloro-5-fluoro-M4-(M-methyl-1,4-benzoxazin-b-yl)" pyrimidineamine is restrained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 6-amino-4-M -methyl-1,4-benzoxazine. IN MO 8.2 (4, 1H), 6.8 (t, 18), 6.75 (t, 1H), 6.60 (t1H), 4.05 (t, 2H), 3.2 (t . 74422 M2-chloro-5-fluoro-M4-(M-methyl-1,4- Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-benzoxazin-7-ip)-nyrimidineamine pyrimidineamine, M2-chloro-5-fluoro-M4-(M-methyl-1,4-benzoxazin-7-i1)-pyrimidinamine is obtained as a result of the reaction of 2.4-dichloro-5-fluoronyrimidine and 7-amino-4-M-methyl -1,4 benzoxazine. IN ЮМ5О 8.2 (a, 1Н), 6.8 (t, IN), 6.75 (i,

IN), 6.60 (t H), 2.05 (pi, 2H), 3.2 (t, 2H) 2.8 (5, ZN) purity 94 95 MS (mass/charge): 295 (MN U ), 7.1.173 M2-chloro-5-fluoro-M44(M-methyl»1,4- Analogous to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenia)-5-fluoro-4-benzoxazin-Z«one -6-yl)-pyrimidinamine of pyrnmidinamine, M2-chloro-5-fluoro-M4-(M-methyl-1,4-benzoxazin-3-on-b-yl)-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro- 5-fluoropyrimidine and compounds b-amino-4-M-methyl-1,4-benzoxazin-3-one, IN ЮМ5О 8.24, 1), 6.8 (t, sem

IN), 6.75 (t, EN), 6.60 (t, H), 4.73 (5, 2H) 2.8 (5, ЗН) purity 96 55 MS 7 o 01 r oesachardny gob (МНЕ 7.1124 M2- chlor-5-fluoro-Х4-(M-methyl-1,4- Analogously to the preparation of 2-chloro-m4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-benzoxazin-3-on-7-yl)- pyrimidineamine pyrimidineamine, M2-chloro-5-fluoro-4M4-(M-methyl-1,4-benzoxazine-Zeon-7-1l)- pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and the compound 7-amino -4-M-methyl-1I,4-benzoxazin-3-one IN OM5O 8.2 (y, 1), 6.8 (pz, (Che) 1NU, 6.75 (t, 1H), 6, 60 (t.15), 4.68 (5, 7H) 2.8 (5, ЗН) purity 93 55 MS (mass/charge); 309 (MIN). b 714125 M2-chloro-M4-(3-ethylcarboxy -4H- Similar to the preparation of 2-chloro-1х4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-imidazo|5,1-c1-1,4-benzoxazin-6-yl)-5-pyrimidinamine, M2- chloro-M4-4(3-stilcarboxy-4H-imidazoi 5,1-c1-1,4-benzoxazin-b-che fluoropyrimidinediamine (K909258) ip)-5-fluoropyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5- of fluoropyrimidine and ethyl-b-zamino-3-carboxy-4H-imidazo 5,1-c1-1,4-benzoxazine, si 1H(DM5 0-46) 8.42 (5, IN), 8.30 (t, IN), 8.05 (t, IN), 7.43 (t, IN), 5.53 (5, 2Н), 4.25 (4, 2Н 1-6.5 Hz), 1.28 (i, 2H, 2-65 Hz), purity 90 95 MS (mass/charge): 390 (Mne). c 7.41.4126 М2-chloro-М4-(3,3-dimethyl»1,4- Analogously to the preparation of 2-chloro-М4-(3,4-etipenedioxyphenyl)-5-fluoro-4-benzoxazin-b-yl)- 5-fluoro-pyrimidinamine | pyrimidine, M2-chloro-Ma-(3,3-dimethyl-1,4-benzoxazin-b-yl)-5-fluoropyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 6-amino-3 ,3-dimethyl-! 4-benzoxazine. IN ЮМ5О 8.184, 1), 6.8 (y, 1), 6.67 (t, 2Н), 3.76 (5, 2Н), 1.05 (5, 6Н) purity 99 95 MS (mass/charge): 309 (MNK) « 741427 2-chloro-5-fluoro-M-P- Similar to the preparation of 2-chloro-Mm-(3,4-ethylenedioxyphenyl)-5-fluoro-4-s-in (methoxycarbonyl)methyl-indazoline- 3-il|- | pyrimidineamine, 2-chloro-5-fluoro-M-| 1-4(methoxycarbonyl)methyl-indazoline-5-1l1-4-c 4-pyrimidinamine (KO35241) pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 5-amino-1-(methoxycarbonyl)methyl-indazoline . IN NMR (0М50-а46): HI 10.04 (5, 18), p » 8.28 (9, 1Н, 1 - 3.5 Gy), 8.12 (5, IN), 8.00 (94 , 1H, 7 1.2 and 4.1 Hz), 7.64 (4, IN, He and 8.8 Hz), 7.58-7.54 (t, 1), 5.39 (5, 2NI ), 3.66 (5, ZN). 71128 2-chloro-5-fluoro-M-(4H-imidazoi2,1-сХН1,4|- | Similar to the preparation of 2-chloro-M-(3,4-ethylenedioxyphenyl)-5-fluoro-4-benzoxazin-8- yl|-4-pyrimidinamine pyrimidineamine, 2-chloro-5-phor-M-(4H-imidazoi2,1-c141,4|-benzoxazin-8-yl| 4» 4IK935257) pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro -5-fluoropyrimidine and 8-(o c amino-4H-imidazo|2,1-cCD.4|-benzoxazine. IN NMR (0M50-06u: IN NMR (OM5O0-46u: 910.08 (5, 18, 8 ,31 (5, HO, 7.91 0, 1H, 2: 2.3 Hz), 7.746, 1H,1 51.2 Gy), with 7.374 IN, 1-23 and 8.8 Gy), 716 (8 , NN, 1-88 Gy), 7.14 (4, 1H, 2 Hz), 5.29 (5, 2H). LC/MS: retention time: 18.74 minutes; purity: 9995; MS (mass/ zaryal): 318 (MNya). 7.1.129 2-chloro-3-fluoro-M-(inlazolin-b-yl)-4- Similar to the preparation of 2-chloro-M-(3,4-ethylenedioxyphenyl)-5 -fluoro-4- (Ce) 42) ko 60 b5 pyrimylinamine (935260) pyrimidineamine, 2-chloro-5-fluoro--(indazolin-b-1l)-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5 -fluoropyrimidine and b-aminoindazole. IN YAM? "SOSIZ): 9 13.03 (5, 18), 10.07 (5, 1H), 8.32 (4 , 1H, 7 - 3.5 Gy), 8.07 (5, 1H)), 7.99 (in, 1H), 7.714, 1H, 1: 8.8 Hz), 7.34 (40, IN, 1 - 1.7 and 8.8 Gy). LC/MS: retention time: 18.52 minutes; purity: 9095; MS (mass/charge): 253 (Mn.yu). 9 7A4.130 2-chloro-5-fluoro-M-(indazolin-5-yl)-4- Similar to the preparation of 2-chloro-1h-(3,4-styrenedioxyphenyl)-5-fluoro-4-pyrimidinamine (K935265) tpyrimidinamine, react 2,4-dichloro-5-fluoropyrimidine with 5-aminoindazole. IN NMR (SOSIZ): 19.99 (5, 1H), 8.26 (4, 1H, 7 - 3.5 Hz), 8.07 (5, 18), 7.990, IN, 2 101 Hz), 7 .53 (44, 2H, 1 2 1.7 and 8.8 Gy). LC/MS: retention time: 18.03 minutes; purity: 9795; MS (mass/charge): 264 (MI).

TAZ 2-chloro-5-fluoro-M H-pyrrol-1-yl)-4- Similar to the preparation of 2-chloro-M-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine (К935275) pyrimidineamine, 2 -chloro-5-fluoro-M-H-pyrrol-1-yl)-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and i-aminopyrrole. IN NMR (SOSIzuU: 211.39 (5,1Н), 8.35 (0, IN, 5 2: 3.5 Hz), 6.83 1, 2Н, 31 -7.3 Hz), 6.07 (6 2Н, 1-23 Gy). PH/MS: retention time: 18.95 minutes; purity: 9750; MC (mass/mass): 213 (MN). 7.1.132 2-chloro-5-fluoro-M4-(3-(1H.-tetrazole-5-) Reaction mixture with 2,4-dichloro-5-fluoro-pyrimidine (1.2 equivalents) and 3-1yl)phenyl |-4-pyrimidinamine (K926853) with (tetrazol-5-yl)anilium (I equivalent) in a solution of methanol:water (1:1 by volume) is heated at 560 °C for 24 hours. After dissolution with water and acidification, the solid formed the fraction is filtered, washed with water, dried and analyzed for the formation of 2-chloro-5-fluoro-7-|134 IN.tetrazol-5-yl)phenyl|-4-nyrimidineamine (K926853). Alternatively, this reaction can be carried out by treating 2,4-dichloro-5-fluoropyrimidine (1 equivalent) with 3-(tetrazol-5-1L)aniline (3 equivalents) in a solution of methanol:water (1:1 by volume ) at 60 oC for 2-3 hours or at room temperature for 24 hours. The reaction product is 2-chloro-5-fluoro-M4-I1341H-letrazol-5-yl)phenyl|-4-pyrimidinamine. IN NMR (OM 50-46): SI 10.25 (v, NU, 8.43 (5, 1), 8.374, 1H,2- 3.6 Hz), 7.90 (44, IN, 1- 0 .9 and 9 Hz), 7.75 (6, 1H, 1-7.5 Gy), 7.51 (0 1H, 1-5 7.8 Gy); LC/MS: purity: 9090; MC (mass/charge): 292 (MN). 1.1.133 2-chloro-Ma-cha-hydroxy-3,4-dihydro-21-1- | A solution of 3,4-dihydro-4-hydroxy-b6-amino-2H-1-benzopyran and 2,4-dichloro-5-fluoro-benzopyran-b-yl)»5-fluoro-? 4" of pyrimidine in MeOH is stirred for 2 hours at 700C. The mixture of pyrimidineamine (K950297) is dissolved in water, and the formed precipitate is filtered to obtain 2-chloro-M4-(4-hydroxy-3,4-lihydro-2H-1-benzopyran-b-yl)-5-fluoro-2,4 - pyrnmidinamine in the form of a solid fraction that has a light brown color. LC/MS: purity: 99.39; MS s (mass/charge): 296.1 (MNK). o 71434 2-khpor-Ma-(4- A solution of 3-(p-aminophenyl)-propionic acid and 2,4-dichloro-5-fluoro-pyrimidine in methoxycarbonylethyleneoxyphenyl)-5-MeEON is stirred for 2 hours at 700C. The mixture is dissolved in water, and the fluoro-2,4-pyrimidinamine (K950375) formed precipitate is filtered in order to obtain 2-chloro-M4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinamine in the form of a solid fraction having a light brown. LC/MS: purity: 93.395; MS (Ce) (mass/charge): 311.98 (M). 7.1.135 2-Chrom-Ma-(3-carboxy-4-hydroxyphenyl)- | A solution of 3-carboxy-4-hydroxyaniline and 2,4-dichloro-5-fluoro-pyrimidine in MON (22) 5-fluoro-2,4-pyrimidicamine (K950298) is stirred for 2 hours at 700C. The mixture is dissolved in water, and the formed precipitate is filtered to obtain 2-chloro-M4-(3-carboxy-4-hydroxyphenyl)-5-he fluoro-2,4-pyrimidinamine in the form of a solid fraction having a light brown color. LC/MS: purity: 87.495; MS (mass/charge): 284.1 (MIN-Y), s 7.141136 2-chloro-M4-(4-trifluoromethyp-3- Solution of 4-trifluoromethyl-3-methoxycarbonylaniline and 2,4-dichloro-5-fluoro- methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidine in MeOH is stirred for 2 hours at 700C. The mixture with pyrimidinamine (2950390) is dissolved in water, and the precipitate formed is filtered to obtain 2-chloro-M4-(4-trifluoromethyl-3-methoxycarbonylpheny)-5-fluoro-2,4-pyrimidinamine in the form of a solid fraction having a light brown. LC/MS: purity: 96.45; MS (mass/charge): 366.34 (MN). 7.414137 2-khpor-M4-4(3-methylcarbonylphenyl)-5- A solution of 3-methylcarbonylaniline and 2,4-dichloro-5-fluoro-pyrimidine in MEOH « fluoro-2,4-pyrimidinamine (K950369) is stirred for 2 hours at 700. The mixture is dissolved in water, and the formed precipitate is filtered to obtain 2-chloro-m4-(3-methylcarbonylpheny)-5-fluoro-2,4-pyrimidinamine in the form of a soluble fraction having a light brown color. - with LC/MS: purity: 99.15; MS (mass/charge): 266.12 (MN). 714138 2-chloro-M4-(3-phenylcarbonylphenyl)-5- A solution of 3-phenylcarbonylaniline and 2,4-lichloro-5-fluoro-pyrimidine in MON h with fluoro-7,4-pyrimidinamine (950370) is stirred for 2 hours at 700С. The mixture is dissolved in water, and the formed precipitate is filtered to obtain 2-chloro-M4-(3-phenylcarbonylphenyl)-5-fluoro-2.4-pyrmidinamine in the form of a solid fraction having a light brown color.

RHLMS: purity: 78.5; MS (mass/mass): 328.16 (Mn. 7.1.139 2-chloro-MA-3-nitrophenyl)-5-fluoro-2,4- Solution of 3-nitroaniline and 2,4-dichloro-3-fluoro- pyrimidine in MEON is mixed with (ee) pyrimidineamine for 2 hours at 700С7. The mixture is dissolved in water, and the resulting precipitate is filtered to obtain 2-chloro-1M4-(3-nitrophenyl)-5-fluoro-2,4-pyrimidinamine in the form of a solid fraction having a light brown color. IN

NMR (PM5OU: s 10.34 (5, 18, 8.73 (40, IN, 1-24 Gy), 7.56-8.29 (kto, 4H). shk 741140 2-chloro-m4-(3 -hydroxymethylene-4- A solution of 3-hydroxymethylene-4-methoxyaniline and 2,4-lichloro-5-fluoro-pyrimidine in methoxyphenyl)-5-fluoro-4-aminopyridine MeOH is stirred for 2 hours at 700°C. The mixture is dissolved in water, and ( Se) 42) ko 60 b5

18950384). LC/MS: purity: 91.895; MS (mass/charge): 256.03 (MN-). background 2-xpor-M4-(3-amino-4-stoxyphenyl)-5- A solution of 3-amino-d-ethoxyaniline and 2,4-dichloro-5-fluoro-pyrimidine in MEON fluoro-4-aminopyridine (5950387) is stirred for 2 hours at 700C. The mixture is dissolved in water, and the formed precipitate is filtered to obtain 2-chloro-M4-(3-amino-4-ethoxyphenia)-5-fluoro-4-aminopyridine in the form of a solid fraction having a light brown color. LC/MS: purity: 93.29; MS (mass/charge): 252.06 (MN-). 72000000 Synthesamine thermocouples 724 5-amino-2-(2-hydroxyacetylenoxy)pyridine; A methanolic solution (50 ml) of 2-(2-hydroxyethyleneoxy)-5-nitropyridine (0.5 g) was hydrogenated for 2 hours in the presence of Ra/C (1095; 0.05 s) using a hydrogen filled flask. After filtering through a celite pad and washing with methanol, the solution is concentrated to obtain 5-amino-2-(2-hydroxyethyloxy)pyridine. IN NMR (SOSIZU; GI 7.58 (0, 1H, 12 3 Gy), 7.05 (49, IN, 7: 2.7 and 8.1 Hz), 6.64 (4, 1H, 2: 8.7 Hzu, 4.36 (pu, 2H), 3.89 (t, 211). 722 4-chloro-3-methoxyaniline Analogously to the preparation of 5-amino-2-(2-hydroxyethyleneoxy)pyridine, as a result of the hydrogenation of 4-chloro- 4-chloro-3-methoxyaniles are obtained from 3-methoxynitrobenzene.

LC/MS: purity: 9895; M: 199 (ME: acetonitrile). 7.2.3 2-15-amino-2-oxo-1,3-benzoxazole-3(2H)- | Analogous to the preparation of 5-amino-2-4(2-hydroxyethyleneoxy)pyridine, as a result of yl|acetamide hydrogenation of 2-P1,3-benzoxazole-2-oxo-5-nitro-3(2H)-yl)acetamide, we obtain 2- ( 5-amino-2-oxo-1,3-benzoxazole-3(2H)-iliacetamide. LC/MS: purity: 9695; MB; 208 (MNY. 124 7-nitro-1,2,3,4-tetrahydroisoquinoline 7 -nitro-1,2,3,4-tetrahydroisoquinoline is prepared by nitration of 1,2,3,4-tetrahydroisoquinoline according to the following method: Ogypehuviyd, Oagu Y..;

Ranapikag, Mah N.; Svidzheii!, Titofu M.; Stizsiope, Kehip V.; /oigpa! Oi Medisipai

SNeptivite (1997), 40125), 3997-4005. 7.2.5 2-(i-butoxycarbonyl)-7-nitro-1,2,3,4. A mixture of 7-nitro-1,2,3,4-tetrahydroisoquinoline (0.55 g, 3.1 mmol), di-yl-tetrahydroisoquinoline butyldicarbonate (0.70 g, 3.2 mmol) and triethylamine (1.0 ml , 7.7 mmol) in dichloromethane (8 ml) is stirred at room temperature for 8 hours,

The reaction mixture is dissolved in water (50 ml) and stirred for | hours

The organic phase is separated and washed with brine. The organic phase concentrate is 2-(1-butoxycarbonyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline, IN se

NMR (SOSIS): 0 8.03-7.95 (t, 72Н), 7.28 (a, 1, 7: 8.4 Gy), 4.66 (5, 2Н), 3.68 (6 2Н , o

7.2.6 2,3-dihydro-b-nihro-4-benzylpyranone 3-(p-nitrophenyl)-propionic acid is dissolved in concentrated sulfuric acid and treated with P2O5. The mixture is stirred for an hour at room temperature and drunk over ice. As a result of filtration, 2,3-dihydro-b6-nitro-4-benzylpyranone is obtained in the form of a white (Te) solid phase. IN NMR (0M50U: 7 8.47 (4, 1 2: 3.0 Hz, IN), 8.35 (44.1 2 3.0, 9.90 Hz, 18), 7.2954.1-90 Hz, NN), 4.706 7: 7.2 Gy, 1), 2.90(,1-:7.2 GP, 18). 7.27 З,4-dihydro-4-hydroxy-6-amino-2Н-1- A mixture of 2,3-dihydro-6-nitro-4-benzopyranone and РО/С (1095) in MEeOH hydrogenates benzopyran at 220С for 3 hours ( 2.7 atm). The mixture was filtered and concentrated to dryness to give 3,4-dihydro-4-hydroxy-b-amino-2H-I-benzopyran in the form of a brown oil. IN NMR (OM5О0Х: ГИ 6.40-6.56 (t, ZNU, 5.05 (Bz, 18), 4.45 (5, IN), 3.94-4.09 (t, 2Н), 1 .76-1.98 (t, 28). sem 7.7.8 Ma-(3,4-ethylenedioxyphenyl)-5- Solution of 2-chloro-5-ethoxycarbonyl-Ma-(3,4-ethylenedioxyphenyl)-2,4 -pyrimidinamine to ethoxycarbonyl-2,4-pyrimidinediamine MVION is treated with a 2590 aqueous solution of MH3. ,4-styrenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidineliamine in the form of a white solid phase.

LC/MS: purity: 92.395; MS (mass/charge): 317.28 (MN, 100). 7.2.5 3-(M.morpholinocarbonyl)aniline In a solution of 3-nitrobenzoyl chloride (0.59 g, 2.7 mmol) and pyridine (0.27 mg, 3.7 mmol) in an anhydrous dichloromethane solution (15 ml) at 02С add morpholine (0.28 ml, 3.2 mmol). The reaction mixture is heated to room temperature and stirred for 20 hours. After removal of the solvents in vacuo, the residue is suspended in ethyl acetate and washed in a solution of 1M HCl. The organic layer is washed with a saturated solution of MansoZ and brine. As a result, and from the removal of solvents in a vacuum, we obtain 1-(M-morpholinecarbonium)-3-nitrobenzene, which can be used without further purification.

A mixture of 14C-morpholinecarbonyl)-3-nitrobenzene (0.64 g) and 1095 Ra on activated carbon mg) is stirred in atm and degassed methane, in carbon (60 mg) in a measured (65 ml) cylinder with H2 for 2 hours. The reaction mixture is filtered through (ee) additional filter material Celite (Seye()), after which it is concentrated under reduced pressure to obtain 3-(M-morpholinecarbonyl)aniline. IN NMR km (SOIU: p 7.19-7.14 (t, 1), 6.75-6.69 (tr, ZNI), 3.58-3.71 (t, 10). 7.2.0 3-( M-propylcarbonyl)aniline Analogously to the preparation of 3-(M-morpholinecarbonyl)aniline, 3-0M--propylcarbonyl)aniline is obtained as a result of hydrogenation of 1-Y(M-SHY (Se) 42) ko 60 b5 propylamino)carbonyl|-3 -nitrobenzene, which is obtained as a result of the reaction of 3-nitrobenzoyl chloride and p-propylamic acid. IN NMR (SIL): 0 7.18 (B, IN, 2" 7.5 Hz), 7.413 1H.21- 1.8 Gy), 7.05-7.1 (t, 18), 6.78 (44, IN, 5 1.2, 2.4, and 7.5 Hz), 6.10 iB5, IN, 3.58-3.53 (B5, 2H)), 3.43-3.34 (t , 2NI), 1.68-1.57 (t, 2H), 0.97 (i, ЗН, 1-72

Gi). 7241 3-(4- Analogous to the preparation of 3-1M-morpholinecarbonyl)aniline, 3-(4- (stoxycarbonyl)piperidinocarbonyl|vni | (ethoxycarbonyl)niperidinecarbonyl)aniline is obtained as a result of hydrogenation of 1-lin Г4-(stoxycarbonyl)piperidinocarbonyl l)-Z- nitrobenzene, which is obtained as a result of the reaction of 3-nitrobenzoyl chloride and stilisone pecotate. 7212 3-(M-methylcarbonyl)aniline Analogously to the preparation of 3-(M-morpholinecarbonyl)aniline, 3-(M-methylcarbonyl)aniline is obtained as a result of hydrogenation of 1-10M-70 methylamino)carbonyl)-3-nitrobenzene, which is obtained as a result reactions of 3-nitrobenzoyl chloride and methylaminohydrochloride. 1H NMR (SOSIS): 27.18 (0, 1H, 1-:7.5 Gy), 7.13 0, 1H, 12 1.8 Hn), 7.04-6.99 (t, 1), 6.81-6.75 (t, 1H), 6.05 (65, 1H), 2.84 (5, 2), 2.99 (4, ZN, 1-4.8 Gy). 72.13 7-amino-tetralone Similarly to the preparation of ethyl 4-aminophenocaseacetate, 7-amino-I-tetrapone is obtained as a result of hydrogenation of 7-nitro-i-tetralone. 1H YAMV (SOSIZ: 0 7.32 (F1NUI- 2.4 Gy), 7.05 (4, IN, 15 8.1 Hz), 6.82 (db, IN, 2e 2.2 and 8.1 Go ), 2.85 (1, 2H, 12: 6.6 Hz), 2.61 (0 2H, 12 6.6 Hz), 2.14-2.04 (t, 2H). 72.14 7-amino- 2-(t-butoxycarbonyl)-1,2,3,4- Analogously to the preparation of 4-aminophenoxyacetate style, 7-amino-2-(t-tetrahydroisoquinoline butoxycarbonyl)-1,23,4-tetragylrhoisoquinoline is obtained as a result of hydrogenation of 2-( 1-butoxycarbonyl)-7-nitro-1,2,3,4-tetrahydroisoquinolin. 2 2.4 and 8.4 Gy), 6.44 (b5, 1H), 4.47 (5, 2H), 3.63-3.48 (t, 2H), 2.711b 2A, 1 5.1 Gy), 1.45 (5.9H). 7.2.15 7-amino-1,2,3,4-tetrahydroisoquinoline Similarly to the synthesis of 4-aminophenoxyanetate, 7-amino-1,2,3,4-tetrahydroisoquinoline is obtained as a result of hydrogenation of 7-nitro-1,2,3, 4- tetrahydroisoquinoline. IN NMR (0M50-46u; 21 9.35 (05, 11), 6.82 a, TAN, 1-81

Gy), 6.45 (44, 1H, 2-24 and 8.4 Gy), 6.30 (4, 1, )--2.4 Hz), 5.05 (5, 28), 4.05 (5, 2H), 3.24 ( 2H, 1-66 Hz), 2.78 (0 2H, 4- 6.6 Ha). 7.2.16 2-(3-aminophenoxy)-M,2- Similarly to the preparation of ethyl 4-aminophenoxyacetate, 2-(3-aminophenoxy)-M,2- dimethylpropanamide dimethylproganamide is obtained as a result of hydrogenation of M,2-dimethyl-243- nitrophenoxy) propanamide IN NMR (SOSIZ3U; si 7.03 (6 1H, 7 7.8 Go), 6.71 (65, Ha 1), 63944, 1H, 1 1.2 and 6.9 Hz), 6.29 (ad , 1H, 7: 2.4 and 9.6 Hz), 6.25-6.22 (t, 180), 2.86 (d, ZN, 1: 4.2 Gy), 2.86 (4, ЗН, 4-4.2 G i), 1.50 (8, 6Н). о 7247 Etnya 2-(3-aminophenoxy)-2- Similar to the preparation of stil 4-amivophenoxyacetate, ethyl 2-(3-aminophenoxy)-methylpropanate 2-methylpropanate is obtained as a result of hydrogenation of stil 2-methyl-2-(3- nitrophenoxypropanate. 1Н YAM (SOSIZ)U: 0 6.99 (b YAN, le 8.7 Gy), 6.32 (ab 1H,

With 1.2 and 7.2 Hz), 6.24-6.18 (t, 2H), 4.23 (d, 2H, 1-7.2 Hz), 1.58 (5, NO), 1 ,24 (, ZY, «se 1-69 Gy). 7.2418 M-methyl-2-(5-imino-2- In contrast to the preparation of ethyl 4-aminophenoxyacetate, M-methyl-2-(5-amino-2- He»! methylphenoxy)acetamide methylphenoxy)acetamide is obtained as a result of hydrogenation of M-methyl -2-(2-methyl-5-nitrophenoxy)acetamide. IN NMR (SZOG)U: I) 6.86 (d, 1H, 7: 7.5 Ga), 6.32-6.25 (t, 2H), 4.43 (5, 2H), 2.82 (5, ZN), 2.14 (c, ZN). ch 7.29 b-amino-2-(methoxycarbonyl)(1H)-indole | 6-Amino-2-(methoxycarbonyl)-(1H)-indole is prepared according to the method given in the following sources: 1. Adatwe, Kisnaga K.; Rge55, )eChegu V.; Juesrap, Eyugata O.; Bupiweis village

Society (1991), 12 (5), 675-681. 2. Voret, Jugier I; In the village of Msiua; Nap, Miapre; D0Bpzop, Yuotsriaz 5.; Bioorganic 5.

Medispa! Spetivig (1995), 3(6), 611-621 7.2.20 Preparation of 3-hydroxy-5-Benzyl M-(3,5-dihydroxyphonyl)carbamate "(metho oxycarboniamethyleneoxy aniline and To a mixture of 5-aminobenzop-I,3- of diol (0.60 g, 3.7 mmol) and hydrogen carbonate and sodium bicarbonate (1.4 g, 16 mmol) in TI F/water (15 ml, 1:1 by volume) were added dropwise to 50 bio( methoxycarboniamethyleneoxy)aniline benzylchloroformate (1.6 mg, 11 mmol). After standing for 3 hours at room temperature, THF is removed in vacuo, and the remaining aqueous layer is removed with ethyl acetate. Purification by column chromatography over silica gel gives benzyl M-(3,5- and dihydroxyphenine) carbamate. TIN NMR (SOZOVO 0 7.42-7.25 (pi, UNI), 6.46 (d0, 2H, 3-х 2,А и), 5, 97-5.94 (t, IN), 5.14 (5, 2H).

Benzyl M-I3-tihydroxy-5-(methoxycarbonylmethyleneoxy)phenyl|carbamate and benzyl

М-И3,5-bis(methoxycarbonyl methyleneoxy)phenyl|carbamate (ог) Analogously to the preparation of ethyl 4-nitrophenoxyacetate, a mixture of benzyl ЙМ-Й 3» hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl|carbamate IN NMR (PM5O-46): si ko 9.62 (v, IN), 9.44 (5, TN), 7.42-7.31 (tt, 5H), 6.63 (5, 1NI), 6.50 (i, 1H, 1 - 2.4 Gy), 5.93 (IN, I1- 2.4 7), 5.10 (5, 2H), 4.63 (5, 2H), 3.67 (5, ЗН), and benznl M-13,5- - bis(methoxycarbonylmethyleneoxy)phenyl|carbamate | H NMR (SOSIS): 1 7.38-7.32 (t, 5H), 6.86 (5, 1H), 6.67 (8, 2H, 1-1.8 Hz), 6.19 IN, 15 2.4 Hz), 5.16 (5.2), 4.57 20 "5, ZNU, 3.78 (5, 6H), (Ce) 42) ko 60 b5 are obtained as a result of the reaction of benznl M-(3, 5-dihydroxyphenyl)carbamate and methylbromoacetate and separated by column chromatography over silica gel.

C-hydroxy-5-(methoxycarbonylmethyleneoxy)aniline

Similarly to the preparation of ethyl 4-aminophenoxyacetate, 3-tihydroxy-5" (methoxycarbonylmethyleneoxy)aniline is obtained as a result of hydrogenation of benzyl M-

3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl|carbamate. IN YAM (SPZO): 0 5.87-5.80 (t, ?2NI), 5.78-5.72 (t, 1), 4.56 (5, 28), 3.76 (z, ZN ). 3,5-bis(methoxycarbonylmethyleneoxy)aniline

Similarly to the preparation of ethyl 4-aminophenoxyacetate, 3,5-bis(methoxycarbonylmethyleneoxy)aniline is obtained as a result of the hydrogenation of benzyl

M-(3,5-bis(methoxycarbonylmethyleneoxy)phenyl|carbamate. 1H NMR(SOZO): C 5.92 (a, 2H, 15 72.4 Hz), 5.83 ( 1H, - 2.4 G and) , 4.58 (5, 4), 3.78 (5, OH). 7.2.21 Ма4-(3,4-ethylenedioxyphenyl)-5- Solution of 2-chloro-5-ethoxycarbonyl-М4-(3,4- ethylenedioxyphenyl)-2,4-pyrimidineamine into ethoxycarbonyl-2,4-nyrimidinediamine is treated with a 2595 aqueous solution of MNH. The resulting mixture (K950287) is stirred for 30 minutes at a temperature of 100°C and purified by flash chromatography over silica gel to form M4- (3,4- ethylenedioxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine in the form of a white solid fraction. LC/MS: purity: 92.39; MS (mass/charge: 317.28 (MH, 100). 7.2 22 Ethyl b-nitro-3-carboxy-4H-imidazo|5,1-| 3-carboxy-4H-imidazoi5,1- | Ethnl b-nitro-3-carboxy-4H-imidazoi 5, 1-c01- 1,4-benzoxazine is reduced with e|-1,4-benzoxazine shaking for 1 hour in MeOH under the pressure of NO, which is equal to 2.7 atm, at 20 weight percent of 10-zone Ra/С (Perivva), after which the solution is filtered, and the solvent is evaporated. The compound is purified directly by column chromatography (ETO Ac/hexane) to give stil-b-amino-3-carboxy-4H-imidazo| 5,1-с1-1,4-benzoxazine IN (0М5О-46) 8.41 (5, 1Н), 6.98 (t, EN), 6.82 (t, 18), 6.43 (t, IN) , 5.28 (5. 2H). 4.23 (94.2Н, 256.2 Hz), 1.27 (4.2Н, 1-62 Gy) purity 92 95; MS (mass/mass): 232 (MN). Ha!

A mixture of 15 g of 2-amino-4-nitrophenol and 40 g of Boc2O is filtered and heated in a reflux flask overnight in 300 ml of SNCIZ, after which the filtrate is evaporated almost to dryness. The residue is ground into a powder compatible with hexane, collected using a vacuum filter and dried with the formation of 2-

M-Vos-amino-4-nirofenoplu. Next, 2-M-Boc-amino-4-nitrophenol is heated in a reflux flask in acetone with 15.6 ml of 1-chloro-2-methylpropene and 25 g of potassium carbonate overnight. The mixture formed as a result of the reaction is poured (Se) into an ice slurry, after which the solid fraction is collected using a vacuum filter and washed with water. The solid fraction is dissolved in EOAc, the organic b) component is washed with 1095% Man solution and saline solution, after which it is dried over Mg5O4. The organic component was filtered to remove the dry substance and evaporated to form 18 g of 1442-M-Boc-amino-d-nitrophenoxy)-2-ac methyl-2-propene. 7.8 g of 142-M-Boc-amino-4-nitrophenoxy)-2-methyl-2-propene is stirred in a methanol solution of HCl in a round-bottom flask with a sem membrane overnight, then heated in a reflux flask at 802

C for 10 minutes, the reaction temperature is reduced, and methanol is removed by evaporation with simultaneous rotation. The residue is dissolved in 30 ml of 4M NS, then poured into a new vessel in order to separate insoluble solid particles, and cooled to 0" C. A solution of 1.83 g of Mamog in 5 ml of water is added dropwise to the solution formed in this vessel and neutralized with the help of solid sodium bicarbonate, Next, a solution of 1.54 g of MaM3 in 17 ml of water is slowly added dropwise to this solution, and " the reaction product is stirred for 30 minutes. The precipitate is collected using a vacuum filter, washed thoroughly with water and dried to give 5, 7 g of 14(2-azido-4-nitrophenoxy)-2-methyl-2-propene. Next, 7 g of I-(2-azido-4-nitrophenoxy).-2-methyl-2-propene is heated overnight in a flask under reflux in 300 ml of benzene, then cooled and evaporated. , which is 5.1 g. From this amount, 1 g is dissolved in 500 ml of MeOH/595 TNE, after which 200 mg of 1095 PO/ C (Redivza) and the resulting mixture are shaken in an NO atmosphere at a pressure of 2 atm for 8 hours. The amount obtained as a result of the reaction is filtered through

Go! the gasket from the cleat, and the solvent is evaporated. The residue is dissolved in the smallest amount of DCM/THF/MeEON and loaded into a column measuring 5 x 20 cm with a saturated solution of MEONLSM 5102. The resulting compound is isocratically eluted with low positive pressure. The resulting fractions are combined and evaporated to give 590 mg b-Zmino-3,3-dimethyl-1,4- shk of benzoxazine. IN (0М850-46) 6.30 (4, 1), 5.75 (9, 1), 5.65 (44, 1), 3.58 (5, 2Н), 20 1.08 (5, A ) purity 99 95 MS (mass/charge); 179 (MN). (Se) 42) ko 60 b5

7.2.25 Ethyl 4-aminophenoxyacetate Ethyl 4-nitrophenoxyacetate

33-Nitrophenol (76.45 g, 550 mmol), K 2 SOZ (76.45 g, 550 mmol) and anhydrous acetone (500 mL) were charged to a dry reflux reactor, M2 inlet, and magnetic stirrer under M2 atmosphere. Ethyl bromoacetate (55.44 mL, 500 mmol) was added at room temperature over 15 minutes. Next, the reaction mixture is heated for 16 hours, after which it is cooled and poured into ice water (4 kg). The resulting aqueous solution was extracted with CH 2 Cl 2 (3 x 500 mL), dried over anhydrous Ma 2 O 4 , and the solvent removed to afford 103 g (9295) of the desired ethyl 4-nitrophenoxyacetate. IN NMR (SUSIZU: Gy 8.204, 2H, 7: 8.2 Gy), 6.95 (4, 2H, 1-28 Hz), 4.72 (8, 2H), 4.25 (9, 2H), 1, 23 (I, ZN); РХ/MS: duration of retention: 27.07 quipins; purity: 10095; MU: 267 (M acetonitrile). 70 Ethyl 4-aminophenoxyacetate

A solution of ethyl 4-nitrophenoxyacetate (15 g) in OH (400 ml) was hydrogenated at a pressure of 2.7 atm for 40 minutes in the presence of 1095 Ra/C (1.5 g, 1095 by weight).

After filtration through celite, the solvent is removed under reduced pressure to form ethyl 4-aminophenoxyacetate. IN NMR (SOSIZU 0 6.77 (y, 2H, 8.1 Hz), 6.60 (0, 2H, 1: 8.0 Gh), 4.50 (5, 2NI), 4.24 (9, 2NU, 1.24 (i, ZN); LC/MS: retention time 75: 12.00 minutes; purity: 10095; MS (mass/charge): 196 (MNK). 7.2.26 Tert-butyl 4-aminophenoxyacetate Tert -butyl 4-nitrophenoxyacetate

Similarly to the preparation of ethyl 4-nitrophenoxyacetate, tert-butyl 4-nitrophenoxyacetate is obtained as a result of the reaction of 4-nitrophenol and tert-butylbromoacetate. TYA NMR (SOSISU HO 8.2 (0, 2H, 1- 8.1 Gy), 6.95 (4, 2H, 12 8.2

Go), 4.50 (5, 2H), 1.42 (5, 9H).

Tert-butyl 4-aminophenoxyacetate

Unlike the preparation of ethyl 4-aminophenoxyacetate, tert-butyl 4-aminophenoxyacetate is obtained as a result of hydrogenation of tert-butyl 4-nitrophenoxyacetate. IN NMR (SRSIZ): 17 6.74 (0, 2H, i 9 Hz), 6.62 (d, 2H, 159

Hz), 4.42 (8.2H), 1.42 (5.983; LC/MS: retention time: 16.35 minutes; purity: 9495; MS (mass/charge): 224 (MH). 7.2. 27 Ethyl Z-aminophenoxyacetate Ethyl Z-nitrophenoxyacetate se

Analogous to the preparation of ethyl 4-nitrophenoxyacetate, stil 3-nitrophenoxyacetate is obtained as a result of the reaction of 3-nitrophenol and stilbromoacetate. 1H YAME Go) (SOSIZ): 7 7.88 (FIN, 22 1.2 and 8.7), 70, 1H, 3-24 Hz), 7.450, 1H, 7: 8.4

Hyd), 7.27 (a 1, 1 2.4 and 8.4 Ga), 4.70 (5, 2EU, 4.29 (4, 2HB 12: 6.9 Gy), 1.30 0, ZN , 2- 6.9 Giu; LC/MS: retention time: 27.28 minutes; purity: 9695,

Ethyl 3-aminophenoxyacetate and e)

Analogous to the preparation of ethyl 4-aminophenoxyacetate, ethyl 3. Ge»! aminophenoxyacetate is obtained as a result of hydrogenation of ethyl 3-nitrophenoxyacetate. IN NMR (SOSIS): 2 7.05 (i, IN, 7-7.2 Hz), 6.30 (t, 3), 4.56 (5, 2Н), 4.25 (0, 2Н, 72 : 7.2 Hz), 1.29 (1, ZN, 22 6.9 Hz); LC/MS: duration or retention: 10.69 minutes; purity: 9695; MS (mass/charge): 196 (MH), 7.2.28 (9-Ethyl 2-(4-aminophenoxy)propionate Analogous to the preparation of ethyl 4-aminophenoxyacetate, (CE) ethyl 2-(4-z.aminophenoxy)propionate is obtained in as a result of hydrogenation of ethyl (3-2-4-

ZB nitrophenoxy)propionate. IN NMR (SOSIS): HI 6.79 (y, 2H), 6.58 (4, 2), 4.60 (p (ee)

TN), 4.20 (f 2), 3.2 (05, NO), 1.45 (y, ZN), 1.22 (5 ZN). 7.2.29 M-methyl 3-aminophenoxyacetamide M-methyl Z-nitrophenoxyacetamide

A mixture of ethyl 3-nitrophenoxyacetate (9.12 g, 40 mmol), methylamine hydrochloride (26.8 g, 400 mmol), and diisopropylethylamine (35.5 mL, 200 mmol) was stirred in

Men (100 ml) in a high-pressure vessel at 90 oC for 5 hours. The reaction products are cooled to room temperature and dissolved in water (1 l).

The solid fraction obtained as a result is filtered, washed with water and dried to obtain the required amount of M-methyl Z-nitrophenoxyacetamide (8 g, 9595). IN NMR SOZIZ; О 7.91 (49, 1Н, 7 1.8 and 8.1 Hz), 7.78 (5 1Н, 1-24 ц Ty), 7.50 (0, 1Н, 32 8.7 Hz, 7, 29 (44, IN, 12: 1.8 and 8.4 Hyd), 6.50 (b, 2H), 4.57 (5, 29), and - 2.95 and 2.93 (25, ZN) ; LC/MS: retention time: 17.54 minutes; purity: 10095;

MC (mass/grain): 211 (MNK).

M-methyl 3-aminophenoxyacetamide

Similarly to the preparation of ethyl 4-aminophenoxyacetate, the required amount of M-methyl 3-aminophenoxyacetamide (5 g, 8620) is obtained as a result of hydrogenation of M-methyl 3-nitrophenoxyacetamide (8 g, 39 mmol). IN NMR(SOYUZOYUU; 7 6.99, 1H, 1-81 Hm), 6.37-0.25 (t, ZNU, 4.41 (v, 2NIU, 2.80 (z, ZNU; RH/MS: retention time: 19.80 minutes, purity: 10095. 7.2.30 2-methoxycarbonyl-3-aminobenzofuran 2-methoxycarbonyl-5-nitrobenzofuran (5926609) - (8926610)

To the suspension of 5-nitro-2-benzofurancarboxylic acid (5 g, 24.15 mmol) in SNOSI? 20 (250 ml) at 0 oC add DMF (0.100 mp), then "SOSI"? (2M in SNOSI?2, 36.23 (Ce) (42) ko 60 b5 ml, 77.46 mia) for 10 minutes. The reaction was quenched with stirring at 9 oC for 1 hour, then continued at room temperature for 30 minutes. The solvent poured into the reaction is removed under reduced pressure, dried in a high vacuum and again overcome with the formation of a suspension in

SNOSIZ (259 ml). The reaction products were cooled to 0 °C, pyridine (4.8 mL, 48.03 mmol) was added, followed by -MeOH (10 mL, excess), and refluxed overnight. The desired 2-methoxycarbonyl-5-nitrobenzofuran (2926609) was obtained as a result removal of СН?СИ2. 1H NMR (SUOSIS): Si 8.66 (y, 1H, 7- 2.4 Hz), 8.36 (89, 1H, 1-24 lta 96 Gy), 7.71 (0.1, 5- 9 .3 Hz), 7.65 (5, 1H), 5.01 (5, ЗН); LC/MS: retention time: 26.94 minutes 2-methoxycarbonyl-5-aminobenzofuran (5926610)

Similarly to the preparation of ethyl 4-amicophenoxyacetate, 2-methoxycarbonyl-5-710 aminobenzofuran is obtained as a result of hydrogenation of 2-methoxycarbonyl-5-nitrobenzofuran (2 g) in MEOH. IN NMR (SOSIiZU: 017.38 (in, 2NI), 6.90 (B, IN), 6.85 (rad, 1), 3.98 (5, ZN). 7.2.31 Methyl 2-(2- methyl-5- Similarly to the preparation of ethyl 4-nitrophenoxyacetate, methyl 2-(2-methyl-5-nitrophenoxy)acetate nitrophenoxy)acetate is obtained as a result of the reaction of 2-methyl-5-nitrophenol and methyl bromoacetate. (46, IN, 2 2.4 and 8.1 Gy), 7.55 (y, 1H, 1-24 Hz), 7.38 (0, IN, /- 8.1 Hz), 4.90 (5, 2H), 3.80 (5, ЗНХ), 2.35 (in, ЗН). 7.2.32 Ethyl 2-methyl-2-(3-Sum of З-nitrophenol (0.50 g, 3.6 mmol), ethyl bromodimethylanetate (0.64 g, 3.3 nitrophenoxy)propanate), K2SOZ (1.3 g, 9.4 mmol) and potassium iodide (catalytic) were heated in absolute alcohol (8 ml) at 709 for 18 hours. as a result of the reaction, the mixture is cooled, poured into a saturated solution of MansSo3 and extracted with dichloromethane. The product of the reaction, ethyl 2-methyl-2-(3-nitrophenoxy)propanate, is obtained after purification by column chromatography on silica gel. IN YAM (SOSISU C 7, 85 (d 1H, 751.2 and 8.1 Hz), 7.68 (6 1H, 1-2 2.4 Hz), 7.40 (1, IN, 2 8.4 Gu, 7.19-7.13 (t, 1H), 4.26 (d, 2H, 32 7 ,2

Go), B.64 (5, 6H), 1.26 (b, ЗН, 2-7.21). 72.33 M-methyp-2-(2-methyl-5-) Similarly to the preparation of M-methyl 3-nitrophenoxyacetamide, M-methyl-2-(2-nitrophenoxy)acetamide methyl-5-nitrophenoxy)acetamide is obtained as a result of the reaction of methyl 2-methyl -5- pytrophenoxysistat and methylamine hydrochloride. 1H NMR (CO3OB); 1 7.82 (44, 1H, 1-24 and 8.1 Gy), 7.69 (0, 1H, 1-24 Hyd), 7.40 (6, 1H, )- 8.1 Hz), 4 .66 (5, 2H), 2.83 (5, ЗН), 2.40 (5, ЗН). c 7.2.34 M,2-dimethyl.2-(3- Analogous to the preparation of ethyl 2-methyl-2-(3-nitrophenoxy)propanate, M,2- o nitrophenoxy)propanamyl. limethyl-2-(3-nitrophenoxy)propanamide is obtained as a result of the reaction of 3-nitrophenol and M.2-dimethyl-2-bromopropanamide (prepared according to the method described in the work of Styligs, Egapk 5., Zg.; Totteh, EBeyikh E. Toshtpa! Oh!

Organic Spetivite (1993), 58(6), 1604-6). IN NMR (SOSIS): GI 7.94 (Fi, 1H, 72 1.2 and 8.1 Gy), 7.78 (6 IN, 3-24 Gy), 7.45 (1, 1H, 24-84 Gi), 7.22 (644, IN, 31.2, 2.4 se and 8.1 Hn), 6.61 (b5, 1), 2.89 (y, ZN, 7- 5.1 Hyd) , 1.55 (5, 6H). 72.35 4 amino-(IN,1,2,3,4- 4-nitro-KI1H,1,2,3,4-tetrazol-5-yl)methyleneoxy |benzene (e») tetrazolyl)methyleneoxy |benzene Mixture 2- cyanomethoxy-4-nitrophenyl (5.8 g, 32.6 mmol), sodium azyl (6.3 g, 98.0 mmol) and ammonium chloride (8.5 g, 163.3 mmol) were suspended in DMF h- (100 ml) containing acetic acid (1 ml), and heat the mixture to 70 2С. After 17 hours, the reaction products are cooled to room temperature and add 2 s

M aqueous solution of hydrochloric acid (100 ml). The solid fraction that falls out as a result of the reaction is collected by filtration, washed with water (2 x 20 3 ml), and then -hexane (30 ml), which as a result forms a compound 4-nitroge)

And H1,2,3,4-tetrazol-5-yl)methyleneoxy |benzene (6.7 g, 9920) in the form of an orange solid fraction: IN NMR (300 MGy, YOM5O-46) 6 8.25 (a, 1-92 Gy, 2H), 7.29 (0.1: 9, I Gu, 2NU, 5.68 (5, 2H); EBI M5 t/h 220 |(SVN7Ch503 -NI|-, 4-amino-(( N,I,2,3,4-tetrazoline)methyleneoxy benzene "

A mixture of 4-nitro-((1.2,3,4-tetrazol-5-yl)methyleneoxy |benzene (6.7 g, 30.4 mmol) and 5-zone (by mass) palladium on carbon (700 ml) is hydrogenated under suspension in ethanol/concentrated hydrochloric acid (14:1, 150 ml) in a hermetic vessel at a pressure of 3.4 atm. The mixture is shaken until the generation of hydrogen stops, after which the reaction products are filtered through infusate earth using chloroform, n and concentrated filtrate to form a crude product. Purification by flash chromatography (7:2-5:0.5 CHCl3/CHNONOClCHNAOH) leads to the formation of 4-amino-(IN, 1,2,3,4-tetrazolyl)methyleneoxy)|benzene in the form of a brown solid fraction: IN NMR (300 MGy, OM5O-y6) 6 6.768, 28.7 Go, 2H), 6.528, -8.7 Gy, 2NU, 5.07 (5, 2NU; EBI M5 t/ g 190 ISVNUM5O -NI-. 7.2.36 4-amino-((1-methyl-1,2,3,4-tetrazole-5- 4-Nitro-Y(1-methyl-1,2,3,4- Tetrazol-3-yl)methyleneoxy|-benzoia and 4-nitro-(2-methyl-(22)yl)methyleneoxy I-benzene 1,2,3,4-tetrazol-5-yl)methyleneoxy |benzene with Mixture of 4- nitro-((1H,1,2,3 4th trazolip)methyleneoxy|benzene (10.00 g, 45.2 mmol), cesium carbonate (22.09 g, 67.8 mmol) and Mei's methyl iodide (7.70 g, 54.3 mmol) were stirred in DMF (200 mL ) at room temperature for 24 hours. shk The mixture of reaction products is concentrated in order to remove most of (Ce) 42) ko 60 b5

DMF, and the crude residue is partitioned between chloroform (100 ml) and water (50 ml).

The organic phase is separated, washed with sodium hydroxide solution, dried (Ma?2504) and concentrated to give the crude product in the form of an orange solid. Purification by flash chromatography (chloroform) leads to the formation of 4-nitro-1(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy |- benzene: IN NMR (300 MHz, OM 50- 46) 6 8.26 (0.3 9.2 Hz, 2H), 7.31 (0.1 92

Gy, 2NU, 5.772 (z, 2H), 4.15 (5, ZN); and also 4-nitro-(2-methyl-1,2,3,4-tetrazol-3-yl)methyleneoxy|benzene: 1H NMR (300 MGo, ЮОМ50О-46) 6 8.24 (8.1-9, 3 Gy, 2H), 71.29 (0, 1: 933 Gy, 2NH, 5.58 (8, 2H)), 4.41 (in, ЗН). 4-amino-1-methyl-1,2,3,4-tetrazole-5-1l)methyleneoxy |-benzene

A mixture of 4-nitro-((1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy|-benzene (3.60 g, 15.3 mmol) and 595 ROS (0.40 g ) is shaken in a 14:1 solution of ethanol In 70 concentrated hydrochloric acid (75 ml) at room temperature under a hydrogen atmosphere at a pressure of 3.4 atm. After shaking the mixture for 4 hours, hydrogen adsorption is stopped. Next, the reaction products are filtered through infusor ground, wash the solids with a 6:3:1 solution of chloroform/metacol/concentrated ammonia, and concentrate the filtrate to form the intermediate 4-amino-CI1-methyl-1,2,3,4-tetrazole-5-ilumethyleneoxy|benzene, which then purified by flash chromatography (95:5 chloroform/methanol): IN NMR (300 MGo, OM5O-46) 5 7.48 (bg5, 2H), 6.79 (4.1 5.9 Hz, 2H), 6.55 (0.1 - 6.9 Hz, 2H), 5.36 (5, 2H), 4.10 (5, ZNO). 7.2.37 4-amino-((2-methyl-1,2 ,3,4-tetrazole-5- A mixture of 4-nitro-((2-methyl,2,3,4-tetrazol-5-yl)methyleneoxybenzene (3.60 g, 15.3 yl)methyleneoxybenzene mmol) and 59o- of Ra/C (0.40 g) is shaken in a 14:1 solution of ether zero in concentrated hydrochloric acid (75 ml) at room temperature in a hydrogen atmosphere at a pressure of 3.4 atm. After shaking the mixture for 3 hours, hydrogen adsorption stops. The reaction products are filtered through infusor ground, the solid fractions are washed with a solution of chloroform/methanol/concentrated caustic ammonia with a concentration ratio of 6:3:1 and the filtrate is concentrated to form the intermediate complex 4-amino-|(2-methyl-1,2,3,4 -tetrazole-5-ylumethyleneoxy |benzene, which is purified by flash chromatography (95:5 chloroform/methanol): 1N NMR (300 MHz, OMI5O-46) 5 6.80 (god 8, 2H), 6.75 ( 4.1 - 9.0 Go, 2H), 6.50 (40, 71.2: 9.0 HY, ЗB), 5.17 (5, 2), 4.37 (5, ЗН). 7.7.38 2 -ethoxycarbonyl-5-aminoindole Similarly to the preparation of ethyl 4-aminophenoxyacetate, 2-stoxycarbonyl-5- (к926611) aminoindole is obtained as a result of hydrogenation of 2-ethoxycarbonyl-5-nitroindole.

Ш РХ/МС: retention time: 13.44 minutes; purity: 9395; MS (mass/charge): 205 7 o m 7.2.39 5-K4-aminophenoxy)methyl|-3-phenyl- Preparation of 5-(4-(nitrophenoxy)methyl|-3-pheny-1,2,4-oxadiazode 12,4-oxadiazole 4-nitrophenol (0.36 g, 2.56 mmol), 5-(chloromethyl)-3-phenyl-1,2,4-oxadiazole (0.5 g, 2.56 mmol) and anhydrous K2SOZ (0.39 g, 2.82 mmol) was dissolved in anhydrous acetone (20 mL) and heated in a flask under reflux for 12 (Ce) hours.The reaction mixture was cooled and the solvent was removed in vacuo.

The intermediate solid fraction formed as a result is collected by (e") filtration, washed with water and dried in a vacuum with the formation of 5-|(4-vitrophenoxy)methyl)|-3-phenyl-1,2,4-oxadiazole (0.70 g, 9295). 1H NMR (SOSISU: 118.25 (b, 2H, 3- 8.8 Sid), 8.08 (44, 2H, 7- 8.2 Ho), 7.52-7.19 (t, ZNU, 7 ,13 (4, 2H, 3-ach 8.8 Gy), 5.45 (5, 2).

Preparation of 5-(4-aminophenoxy)methyl-3-phenyl-1,2,4-oxadiazole se 5-|(3-nitrophenoxy)methyl|-3-phenyl-1,2,4-oxaliazole (0.5 g, 1.68 mmol) is dissolved in a mixture of methanol and methylene chloride (1:1) (120 ml). Next, an aqueous solution (15 ml) of sodium hydrosulfite (0.88 g, 5.05 mmol) and K2SOZ (0.70 g, 5.06 mmol) are added in portions over 10 minutes under a nitrogen atmosphere. The mixture is stirred at room temperature. After the consumption of the initial material, the mixture of reaction products is concentrated and dissolved in water in order to form a homogeneous layer. The aqueous layer is extracted several times with ethyl acetate and methylene chloride. The whole organic layers are combined, dried with anhydrous Ma2504 and concentrated. Purification of the solid concentrate by silica gel chromatography leads to the formation of 5-I(4-s aminophenoxy)methyl|-3-phenyl-1,2,4-oxadiazole (0.23 g, 5195). IN NMR (SOSIS): c 08.11 (t, 2H), 7.52-7.46 (t, ZN), 6.87 (9, 2H, 7-8.8 Gy), 6.54 (4 , 2H, 1- 8.8 Hz), 5.26 - (5, 2H), 3.49 (Bg 5, 2H). p

Preparation of 5-1(4-nitrophenoxy)methyl)-3-methyl-1,2,4-oxadiazole

A mixture of 4-nitrophenoxyacetic acid (2.25 g, 11.4 mmol), apetamidoxime, triethylaminohydrochloride (3.85 g, 27.62 mmol), EHUOSI.HCII (4.37 g, 22.79 mmol)

Go | and diisopropylethylamine (7.42 g, 57.40 mmol) in anhydrous TNE (250 mL) were heated in a reflux flask for 18 h. The inhomogeneous mixture of the reaction products, which has a brown color, is quenched with water and extracted with BOAs (3 x 300 ml). The combined organic layers are successively washed with an aqueous solution of MansSoOZ and brine, after which they are dried over anhydrous Ma?2504. Removal of the solvent and purification by chromatography leads to the formation of 5-(4-nitrophenoxy)methyl|-3-methyl-(Ce) 42) ko 60 b5

1,2,4-oxadiazole (1.52 g, 60 923. 18 UM (SOSISU: 718.24 (a, 2H, y- 8.8 Hz), 7.08 (40, 2, 3- 8.8 Guide), 5.36 (in, 2NI), 2.44 (5, ZN).

Preparation of 5-((4-aminophenoxy)methyl-3-methyl-1,2,4-oxadiazole

Similarly to the preparation of 5-((4-aminophenoxy)methyl-3-phenyl-1,2,4-oxadiazole, 5-I(4-aminophenoxy)methyl|-3-methyl-1,2,4-oxadiazole is obtained as a result of the reaction 5-(4-nitrophenoxymethyl)-3-methyl-1,2,4-oxadiazole and an aqueous solution of sodium hydrosulfite and K2СО3. IN NMR (SOSISU: Г16.82 (4, 2Н, 1- 8.8 Гн), 6, 63 (a 2H, 12 88 Hz), 5.15 (5, 2), 3.38 (g 5, 2), 21 (c, 3H). 7.2.40 Ethnl 2-(4-aminophenyl)-2- Ethnl 2-methyl-2-(4-nitrophenyl)propionate methyl protonate Dry reactor charged with ethyl 4-nitrophenyl acetate (5.0 g, 23.89 mmol), iodomethane (8.48 g, 3.72 mL, 59.74 mmol) ), 18-crown-b (1.57 g, 5.93 mmol) in anhydrous THF (200 ml), cooled to -78 °C in a nitrogen atmosphere. While stirring the mixture, 4"ViOK (5.90 g, 572 .57 mmol).

The resulting purple lull is stirred at a temperature of -78°C for 2 hours, after which the mixture is heated to room temperature. The reaction products are stirred at room temperature for b hours. At this time, as soon as the mixture cools to -78 °C, a second portion of iodomethane, Y-VIOK and 18-crown-6 are added to it and further stirred at the same temperature for 2 hours. The reaction product is slowly heated to room temperature and left to flash overnight. The reaction products are sharply cooled with a saturated aqueous solution of МНАСИ (75 ml), and the resulting homogeneous mixture is extracted with ether (4 x 200 ml), dried over anhydrous Ma?2504 and concentrated. The concentrate is purified by silica gel column chromatography with 195% EEOAc/hexane to give stil 2-methyl-2-(4-nitrophenyl)propionate as a light yellow oil (2.38, 4296). MH NMR(SOSIS): 7 8.17 (a, 2, 7: 8.8 Hz), 7.49 (d, 2H, 1-88 gy), 4.12 (di, 2H, 7-2 7, 0 Sy), 1.60 (5, 58), 1.17 (i, ZN, 72 7.0 Hz).

Ethyl 2-(4-aminophenyl)-2-methylpropionate

Similarly to the preparation of 4-aminophenoxyacetate, ethyl-2-44-aminophenyl)-2-methylpropionate is obtained as a result of hydrogenation of ethyl-2-methyl-2-44-nitropheny)propionate. "H NMR (SOSIS): 117.16 (d, 2H, 3 8.8 Gy), 6.03 (4, 2H, 35 8.8 Hn), 4.09 (46, 2H,, 72 7.0 Hn), 3.62 (Bg 5, 2H)U, 1.52 (8, 6H), 1.17 (i, ZN, 22 7.0 Ho). c 7.2.4 Anilines mixed with components 1,3, 4- | M'"1-(3-chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide oxadiazole He)

To a solution of Z-chlorobenzohydrazide (1 equivalent) and pyriline (2 equivalents) in

A solution of 3-nitrobenzoyl chloride (1 equivalent) in CH2CI2 is added to CH2CI2 at 0 oC and stirred at 0 oC for 1 hour, after which it is left to stir at room temperature overnight. The resulting solution in (Ce) is concentrated and dissolved in water, transferred to alkali with the help of MansSo3, the solid fraction is filtered, washed with ash, dried and analyzed for the formation of IM" 14"3-chlorobenzoyl)-3-(22) nitrobenzene-1- of carbohydrazyl, IN NMR (PPM50-y465U: I 10.99 (5, 1H), 10.79 (in, 18), 8.73 (O5, 1H), 8.43 (BLA4, IN, 1-1.2 and 8.1 Gy), 8.33 (644, 17, 4-8.4 Gy), 7.95 (5, IN), or 7.87 (t, 2H), 7.67 (544, 1H, 32 1.2 and 8.1 Hz), 7.57 (0 18.7- 7.8 Ha); LCMS: purity: 8590; MS (mass/charge): 320 (MNK). c (2-(3-chlorophenyl )-1,3,4-oxadiazol-5-yl|-3-nitrobenzene 3o A suspension of M'"1-(3Z-chlorobenzoyl)-3-nitrobenzene-1-carbohydrazide (0.321 g) in ROSIZ with (3 ml) is stirred at 90°C for 24 hours.The resulting clear solution is rapidly cooled with ice water, and the resulting solid fraction is filtered, washed with water, dried, and analyzed for the formation of |2-(3-chlorophenyl)-1,3,4-oxadiazole-5 -1l|-3-nitrobenzene. IN NMR (OM5O-yb): P 8.86 (1, 1H, 4- 1,8 Gy)), 8.59 (1, 1H, 1 1.8 and 8.4 Hz), 8.48 (t, 1), « 8.25 1H, 121.8 Go), 8.16 (F,1H, 7- 1.2 and 7, 5 Gy), 7.93 (18, 3-8.1 HZ), 7.75 (t, 1H), 7.66 (0, 1H, 1- 7.5 Gy), VK/MS: purity: 8695 ; MS (mass/charge); 302 (МН), шщ с Reduction of (2-4(3-chlorophenyl)-1,3,4-oxadiazole-5-17)-3-nitrobenzene

Hydrogenation of |2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl|-3-nitrobenzene (0.2 g) according to » using 1090 RO/S (0.04 g) in MeOH (200 ml) under pressure | ATM. inches for 1 hour leads to the formation of a mixture of two products, namely: 3-amino-(2-(3-chlorophenyl)-1,3,4-oxadiazol-5-yl|benzene and 3-amino-(2- of phenyl-1,3,4-oxadiazol-5-yl)benzene, which are separated by silica gel column chromatography using n-hexanes, and then a mixture of n-hexanes and 5-1095-EHUOAc solvent. 3-amino-(2 -(3-chlorophenyl)-1,3,4-oxadiazole-5-ylbenzoic acid: 1H NMR (PM 5O-46): I 8.08 (t, 2NI), 7.64 (t, 4H), 7, 42 (t, 1H), 7.10 (t, INU;

LC/MS: purity: 8290; MS (mass/charge): 272 (MN). 3-Amino-(2-phenyl-1,3,4-co oxadiazol-5-yl)benzene: 1N NMR (0M50-a6): 7 8.13 (pt, 1H0U, 7.54 (t, 5NI), 7.30 (t,

TNU, 6.86 (480, 1H, 1-1.5 and 8.1 Gy); LC/MS: purity: 9395; MS (mass/charge): 238 -k (MN.

AI | 1 1-(ethoxycarbonylmethylenecabonyl)-3-nitrobenzene-I-carbohydrazide (Ce) 42) ko 60 b5

Similarly to the preparation of M" 1-(3-chlorobenzoyl)-3-nitrobenzene- | -carbohydrazide,

M'14(ethoxycarbonylmethylenecarbonyl)-3-nitrobenzene-1-carboxylazide is obtained as a result of the reaction of 3-nitrobenzoyl chloride and ethoxycarbonylmethylenecarbohydrazide. YIN YAM? (SOZOYU): G18.74 (t, 1), 8.44 (49,

IN, 18 and 8.1 i), 8.25 (vd, 1H, 3-84 Gy), 7.76 (6 1H, 372 8.4 Hz, 5.22 (4.2H, 1- 65

Gy), 3.44 (B5, 2H), 1.29 (i, ZN, 72 6.8 Gy); LC/MS: purity: 9390; MS (mass/charge: 296 (MN). (2-(Ethoxycarbonylmethylene)-1,3,4-oxadiazol-5-yl|-3-nitrobenzene

Similarly to the preparation of (2-13-chlorophenia)-1,3,4-oxadiazol-5-yl-3-nitrobenzene, (2-(stoxycarbonylmethylene)-1,3,4-oxaliazol-5-yl|-3-nitrobenzene is obtained as a result of the reaction of ROSIZ and M" I-(ethoxycarbonylmethylenecabonyl)-3-nitrobenzene-1-70 carbohydrazide. IN NMR (SOSIZ): С 8.88 (1, 1Н, 12 1.8 Hz), 8.42 (t, 2H), 7.74 (

IN, ze 7.5 Hz, 4.27 (9, 2H, 12: 7.2 Gy), 4.08 (5, 2H)), 1.31 (i, ЗB, 72 7.2 Go); LC/MS: purity: 9595; MC (mass/charge): 278 (MN). 7.2.A2 Synthesis of ()-5-amino-(2,3-dihydro-2" 2-methoxycarbonyl-5-nitrobenzofuran methoxycarbonylbenzofuran Mixture of 2-carboxy-5-nitrobenzofuran (2.0 g), MEON (19 ml) and concentrated

H2504 (2.1 ml) is heated in a sealed tube at a temperature of 600C for

From hours After cooling to room temperature, it is quickly cooled with ice water and carefully restored by MansSoOZ freezing. The resulting solid fraction is filtered, washed with water, dried and analyzed for the formation of 2-methoxycarbonyl-5-nitrobenzofuran. IN

NMR (SrIII): 0 8.66 (4, 1H, 7e: 2.4 Hyd), 8.365 (46, 1H, 7- 2.4 and 9.6 Hz), 7.71 (4, 1H, 1T- 9.3 Go), 7.65 (5, IN), 4.01 (5, ZNU; RHLMS: purity: 9795; MS (mass/charge): 222 (MN). (9)-5-amino-( 2,3-dihydro-2-methoxycarbonyl)benzofuran

A suspension of 2-methoxycarbonyl-5-nitrobenzofuran (2.0 g), 10905 Ra/C (2.0 g) and

Ma2504 (2.0 g) in MeOH (500 ml) was hydrogenated at a pressure of 3.7 atm for 3 days.

The resulting solution is filtered through a pad of celite, concentrated and purified by chromatography using n-hexanes, and then a mixture of 1095%, 2099% EuFAs and n-hexanes with the formation of (H-5-vmino-(2,3 -dihydro-2-methoxycarboyl)benzofuran. 1H NMR (SOSIS); 0 b.69a tn, 8.1 Gy), 6.56 (4, 1H, 1: 1.2 i), 6.48 (ad, IN , Ag 1.8 and 7.5 Hz), 5.14 s (49, 1H.3-6.6 and 7.2 Hn), 3.795, ZN), 3.47 (aa, IN, /- 10.5 and 10.65 Hz), 3.26 (4.18, 1-72 tab, Hn); LC/MS: purity: 10095; MC (mass/charge): 194 (MN). o 7.2.43 3-11-bis(stoxycarbonyl)ethoxy|aniline Preparation of diethyl-2-methyl-2-(3-nitrophenoxy) malonate

Diethyl-2-bromo-2-methylmalonate (1.0 g, 3.95 mmol) was added to a stirred suspension of sodium fluoride (0.57 g, 9.8 mmol) in anhydrous DMF (5 mL). After stirring for 20 minutes at room temperature, 3-nitrophenol (0.55 g, 3.95 mmol) was added to the mixture (Che) zo. The resulting mixture is stirred at 60 °C for 6 hours, cooled to room temperature, dissolved in water (30 ml) and extracted with ethyl acetate (3 x 200 ml). The organic layer is washed with an aqueous solution M

Mahon (2 x 75 ml), dried over anhydrous Ma2504, filtered and evaporated in vacuo to give diethyl-2-methyl-2-(3-nitrophenoxy)malonate (0.89 g, 80950),

IN NMR (SOSIS): 0 7.92 (α, 1Н, 1 - 2.3 and 8.2 Gy), 7.82 (b IN, 1 2.3 Hz), 7.4 I, se

IN, 1-8.2 Hz), 7.30 (d4, IN, 2-23 and 8.2 Hz), 4.28 (di, JAN, 1 - 7.0 Hz), 1.81 (5, ZI), 1.226 (.6Н, 1 - 7.0 Gy). co

Preparation of 3-|1-bis(ethoxycarbonyl)stoxy|aniline

Diacetyl-2-methyl-2-(Z-nitrophenoxy)maloate 10.75 g, 2.40 mmol) is dissolved in a mixture of toluene and stanol (1:1, 100 ml) in a nitrogen atmosphere using a shaker containing Ra/s (0.15 g) and anhydrous Ma2504 (5.0 g). The resulting amount is treated with hydrogen (at a pressure of 7 atm) until diethyl-2-methyl-2-(3-nitrophenoxy)malonate disappears (2 hours). The sumyl is filtered through celite coated with anhydrous Ma2504, after which the pellet pad is washed with EOAc. Next, the filtrate is concentrated and dried in a vacuum to form the required amount of 3-|1-bis(ethoxycarbonyl)stoxyanipine. 16 NMR (SRSISU C 6.98 (B1H, 1 - 8.2 Gy), 6.17-6.28 (t, ЗН), 4.26 (d, 4H, 1 2 7.0 Gy), 3, 65 (bg 5, 7NU, 1.72 (5, ЗН), x z» 1.2А(66Н, 1-70 Hz). p 7.2.4 Preparation of 4-(4-aminophenoxymethyl)- / Preparation of 4-(4 -nitrophenoxymethyl)-2-methoxycarbonyl-furan 2-Methoxycarbonyl-Furan A mixture of 3-nitrophenol (1.0 g, 7.19 mmol), methyl 5-(chloromethyl)-2-furoate (1.38 g, 7.90 mmol ) and anhydrous K2SOZ (1.19 g, 8.60 mmol) in acetone (30 mL)

Go! heated in a reflux flask for 8 hours. The sump obtained as a result of the reaction is cooled and dissolved in water. The solid fraction formed during evaporation is filtered, washed with water and left to dry overnight to obtain 1.81 g (9025) of the required product. IN NMR (SOCI3); 7 7.869, 1H, 1-23 and 8.2 7), 7.800 1H, 3-23 Hz), 745 NO shk 82), 7.27(44.1H,7-23 and 8.2sh),7.17(4 ,1Н,1-3.5 Hz), 6.580, 1Н, 7 - 3.5

Hz), 5.13 (5, 2NI), 3.90 (5, ЗН). (Se) 42) ko 60 b5

Preparation of 4-(4-aminophenoxymethyl)-2-methoxycarbonyl-furan

Similar to the preparation of diethyl-2-methyl-2-(3-nitrophenoxy)malonate, 4-4. nitrophenoxymethyl)-2-methoxycarbonylfuran is reduced to form 4-(4-aminophenoxymethyl)-2-methoxycarbonylfuran. , 1 2: 8.2 Gy), 6.50 (4, 1H, 1 2: 3.5 Hn), 6.37-6.27 «t, ЗН), 5.01 (5, 2H), 3 ,89 (5, ZN). 72.45 Preparation of b-amino-1- Preparation of !-(methoxycarbonyl)methnl-b-nitroindazole (methoxycarbonyl)m indazoline To a solution of 6b-nitroindazoline (2.0 g, 12.25 mmol) in anhydrous DMF is added

CO2 (1.84 g, 13.31 mmol) and methyl 2-bromoacetate (2.04 g, 13.33 mmol).

The resulting slurry is stirred at room temperature for 12 hours. The mixture obtained as a result of the reaction is quickly cooled with water, and the resulting solid fraction is collected by filtration, washed in excess water and air-dried. The collected yellow solid fraction is purified by silica gel column chromatography, using a gradient mixture of solvents with the formation of two products. The required product (1.12 g, 4196) with a high value of BE on TLC is obtained using mixtures

Z0by OA and hexanes.

Similarly to the reduction of distyl-α-methyl-2-(3-nitrophenoxy)malonate, 1-(methoxycarbonyl)methyl-b-nitro-inlazoline is reduced to form b-amino-1-(methoxycarbonyl)methylinlazoline. 1H NMR (SOSIZ3): HO 7.73 (4, 1H, I -.1 Ho), 7.359, 1H, 7 2 8.2 Hyd), 6.49 (44, IN, 3- 1.8 and 8, 8 Gb), 6.39 (5, 1H), 5.34 (Bg 5, 2H), 5.10 (5, 2H), 3.64 "5, ZN).

Preparation of 1-(methoxycarbonyl)methyl-5-nitroindazoline

Similarly to the preparation of 1-(methoxycarbonylmethylb-nitroindazoline), 1-(methoxycarbonide)methyl-5-nitroindazoline is obtained as a result of the alkylation reaction of 5-nitroindazoline with methyl-2-bromoacetate in the presence of K2SOZ.

Required product 1.34 g, 4695) with a high value of KG on TLC in 3096

VO: Hexanes are collected by purification using silica gel column chromatography. IN NMR (SOSISU: 2 8.75 (9, 1H, 71: 1.8 Hn), 8.30 (49, 1H,

CT- 2.3 and 8.2 Hz), 8.26 (5, 1H), 7.404, 1H, 21 -8.2 Hz), 5.22 (5, 2H)), 3.78 (8, ЗН ).

Preparation of 5-amino-1-(methoxycarbonyl)methylinlazoline

Similarly to the preparation of diethyl-2-methyl-2-(3-nitrophenoxy)malonate, 1-se (methoxycarbonyl)methyl-5-nitro-indazoline is reduced to form 5-amino-1-(methoxycarbonyl)methylindazoline. IN NMR (SOSIZU O 7.64 (0, 1, 1-23 Gy), 7.155 (48,1H, 1 2: 8,8 Hz), 6,95 (0, 1H, 1--2,3 Gy) , 6.88 (09, IN, 7 22.3 and 8.8 Gy), 5.09 (5.25), 3.73 (5, ZN).

Preparation of 1-(2-ethoxycarbonylethyl)-b-nitroindazoline

Similarly to the preparation of 1-(methoxycarbonyl)methyl-b-nitroindazoline, 1-re)(stoxycarbonyl)ethyl-b-nitroindazoline is obtained as a result of the alkylation reaction of b-nitroindazoline with ethyl 3-bromopropionate in the presence of K2SOZ. The required (c! product (5895) with a high CI value on TLC in 30 mL of EtOAc: hexane was collected by purification using column chromatography over h: silica gel. IN NMR (SPSISU: HI 8.49 (5, 18), 8 .12 (5, 1), 8.01 ad, 1H, 251.7 and 8.8 C), 7.82 (4, 1H, 2 8.8 Hz), 4.74 (6 2H, 1 and 6 ,4 Hz), 4.09 (o, 2H, 1 2: 7.0 Gy), 3.03 (02, 1-64 Gy), 1.18 (0, ZN, 1 - 7.0 Gyu. s

Preparation of b-amino-| "(2-ethoxycarbonidetyl)i ndazoline so

Similarly to the preparation of distyl-2-methyl-2-(3-nitrophenoxy)malonate, 142-ethoxycarbonylethyl)-b-nitroindazoline is reduced to form 5-amino-1-(2-ethoxycarbonylethyl)indazoline. IN NMR (SOSIZ): 0 7.81 (5, 13), 7.464, 1H, 4 - 8.8 Hz), 6.60 (arr 5. 1), 6.55 (49, 18, 7 -2.3 and 8.8 Gy), 4.512, 7-70 g), 4, (db 2H, 1-70 Gy)), 3.52 (bg 5, 2H), 2.91 (6 2H, 4 - 7.0 Go ), 18 (6 ZN, 3 "7.0 Sy). "

Preparation of 1-(2-ethoxycarbonylethyl)-5-nitroindazoline

Analogous to the preparation of 1-(methoxycarbonyl)methyl-5-nitroindazoline, 1-(ethoxycarbonyl)ethyl-5-nitroindazoline is obtained as a result of the alkylation reaction of 5-nitroindazoline and ethyl-3-bromopropionate in the presence of K2SOZ. The required h product (4395) with a high value of CI and TLC in the 3095th solution of EOAc; and » texanes are collected by purification using silica gel column chromatography. IN NMR (SOSIZ): HI 8.704, 1Н, 7 -1.7 GP), 8.27 (094, 1Н, 1-2.3 and 8.8 b), 8.204, 1Н, 11.7 3, 7.594, 1H,1- 8.8 Hz), 4.70 0, 2H.1-:6A4Gy), 4.07(f,2H, 1-70), 301 (62H, 31-64 g 16 (ZH, 1-70 g (ee) Preparation of 5-amino-1-(2-ethoxycarbonylethnyl)i ndazoline

Similarly to the preparation of diethyl-2-methyl-2-(3-nitrophenoxy)malonate, 1402- ethoxycarbonyl)-5-nitroipdazoline is reduced to form 5-amino-1-(2-ethoxycarbonylethyl)indazoline. 1 NMRSOSIZ)U: 7.78 (5.183, 7.30(d,1H, 3rd 8.8 Gy), 6.914, IN) - 2.3 Sv), 6.87 (40, EN, U - 2 ,3 and 8.8 Gy), 4.59 (0, 2H, 1 64

Gy), 4.08 (where 2H, 7 - 7.0 Gy), 3.02 (g 5, 23), 29206 2H. 1:70 Gi), BIb(b NI g (Se) 42) ko 60 b5

7.0 Gy).

Preparation of 5-amino-2-methylindazoline

Analogous to the preparation of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, commercially available 2-methyl-5-nitroindazoline is reduced to form 5-amino-2-methylindazoline. IN NMR (SOCI3): 1 7.61 (5518), 7.534, 1H, 7 - 8.8 Gy), 6.81 (44, IN, 1 2: 2.3 and 8.8 Gy), 6.75 (0, 1H, 1 22.3 Hyd), 4,E3 (5, ZNU, 3.85 (bg 5, 28). 7.2.46 Preparation of methyl 3-methoxy-4-((6-) Similarly to the preparation of distil-2 -methyl-2-(3-nitrophenoxy)malonate, methide-3-nitroindazol-1-hl)methyl|benzoate methoxy-4-|(b-nitroindazol-1-yl)methyl|benzoate are reduced in order to form methyl 4-( (6-aminoindazol-1-yl)methyl|benzoate. IN NMR (SUSIS): HI 7.88 (5, IN), 75340, IN, 1 - 8.8 Ho), 7.51 (40, 1.3 8.8 Hz), 7.504, 1H, 1.7 Hz), 6.67 (4, 1H, 7 - 8.8 Hz), 6.56 (44, IN, 3 - 1.7 and 8.8 Hz ), 6.454, 1, 7/2: 1.2 Hz), 5.50 (5, 7H), 3.94 70 (5, ZN), 3.87 (5, ZN), 3.79 (Be 5 , 2H).

Preparation of methyl 4-|(b-aminoindazol-2-yl)methyl |benzoate

Similarly to the preparation of distyl-2-methyl-2-(3-nitrophenoxy)malonate, methyl 3-methoxy-4-((b-nitroindazol-2-ylmethyl)benzoate is reduced to form methyl 4-((6-aminoindazol-2- yl)methyl|benzoate. 1H NMR (SOSISU: Pi 7.78 (5, 1H), 7.56-7.53 (t, 2H), 7.43 (40, 1H, 3 - 8.5 Gy), 5.98 (a, IN, 7 - 8, 2 Hz), 6.81 (arr 5, IN), 6.58 (dd, IN, )-- 1.8 and 8.8 Hz, 5.53 (5, 2NI), 3.91 (5, ZN ), 3.89 (5, ЗН). 7.2.47 Preparation of b-amino-1-(2-methoxy-4- Preparation of b-nitro-1-(2-methoxy-4-(0- (o-toluenesulfonamidocarboxy) benzyl|indazoline toluenesulfonamylcarboxy benznliind Complex ester hydrolysis of methyl-3-methoxy-4-((6-nitroindazol-1-nu yl)methyl|bSenzoate in the presence of НОН:НОО leads to the formation of the corresponding acid. The acid obtained in this way (1.65 g , 5.04 mmol) was converted into the acid chloride by reaction with 5OHCl2 (3.68 mL, 50.45 mmol) at reflux for 5 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. O-toluylbenzenesulfonamide (0.95 g, 5.54 mmol) and 4-(dimethylamino)-pyridine (0.67 g, 5.54 mmol) are sequentially added to the acid chloride concentrate dissolved in anhydrous SOHC (75 mL) at at room temperature, and then stirred for 12 hours. The mixture obtained as a result of the reaction is concentrated, dissolved in EtOAc (709 ml) and successively treated with a solution of 2 M HCl (2 x 100 ml), water (150 ml) and sodium chloride solution (190 ml). Typical work-up and purification by silica gel column chromatography afforded the final product (1.57 g, 6425). IN NMR (VM50-46): Г8.75 o (5, 1), 8.31 (5, 1), 8.00 (y, 1Н, 7 2 8.8 Hz), 7.95-7.91 (t, 2H), 7.50 (4.1H, 21.2

Hz), 7.46-7.27 (t, 4H), 6.92 (y, 1H, 72 7.6 Gy), 5.76 (8, 2H), 3.81 (5, ZNI, 2, 54 (5, ZN).

Preparation of 6-amino-1-(2-methoxy-4-(0-toluenesulfonamidocarboxy)benzyl|ndazoline

Similarly to the preparation of distyl-2-methyl-2-(3-nitrophenoxy)malonate, b-nitro-1-(se) | 2-Methoxy-44(o-toluylsulfonamidocarboxy)benzylindazoline is reduced with the formation of b-amino-1-(2-methoxy-44(o- (e") toluylsulfonamidocarboxy)benzyl|indazoline. 1H NMR (SOSIS): C 7.96 (44, 1H, 1-1.2 and 8.2 Gy), 7.76 (5, 1NU, 7.51 (4, 1H, 7 - 1.2 Hz), 7.49-7.44 (t , EN), 7.37 (4.28, «- 1-88), 7.34-7.32 (t, 1H), 7.30 (d, 1H, / - 8.8 Hz), 6, 51-6.47 (t, 2H), 6.35 (5, 1H), 5.35 (5, 2H1I), 3.89 (5, ЗН), 2.54 (5, ЗН).

Preparation of methyl 3-methoxy-4-I(5-nitroindazol-|-yl)methyl|benzoght

ZB Similarly to the preparation of methyl-3-methoxy-4-1(b-nitroindazol-1-(ee)yl)methyl|benzoate, methyl-3-methoxy-4-|(5-nitroindazol-1-yl)methylbenzsate is obtained as a result alkylation reactions of 5-nitroindazoline and methyl-(4-bromomethyl)-3-methoxybenzoate in the presence of K2SOZ. The required product (4705) with a high value of BC on TLC in a 3095 solution of EIOAc: hexanes is obtained as an eluent during purification using the method of column chromatography on silica gel. IN NMR (SOSIZU 018.73 (4, IN, 7 - 1.8 Hz), 8.26-8.22 (13, 218), 7.56 (85, 1NU, 7.54 (ab, IN, 1 -18 and 8.2 Gy), 7.494, 1, 1-94 Gy), 6.984, 1Н, 1-82 Hz), 5.66 (5, 2Н), 3.91 (in, ЗН), 3.89 (5, ZN). Low KE value: methyl-3-methoxy-4-((5- - with nitroindazol-2-yl)methyl|benzoate.

Preparation of 5-nitro-1-(2-methoxy-4-40-h z» toluylsulfonamidocarboxybenzyl|indazoline p

Similarly to the preparation of 6b-nitro-1-(2-methoxy-4-(0-toluylsulfonamidocarboxy benzylindazoline), 5-nitro-1-12-methoxy-4-(0-toluylsulfonamidocarboxy)benzyl|indazoline is prepared from methyl-3-methoxy-4 -Y(5-nitroindazol-1-1l)methyl|benzozta. IN NMR (0M50-46): HIV, (4, 1H, 7-2 2.3 Hz, (ee) 8.395, 1), 8.21 ( 44, 1, 3 - 1.8 and 5.5 Gu, 7.87 (49, 24, ) - 3.6 and 8.8 Hz), 7.48 (y,

IN, 1.2 Gy), 7.39 (49, 1H, ) i 1.2 and 8.2 Gy), 7.33-7.15 (t, ZH), 6.85 (6, 1H, 12 82 km Gy), 5.65 (5, 2H), 3.76 (5, ZN), 2.49 (5, ZN).

Preparation of 5-amino-I-(2-methoxy-44(0-coch toluenesulfonamidocarboxt)benzylindazoline

Similarly to the preparation of b-amino-1-(12-methoxy-4--o- (Ce) 42) ko 60 b5 -1і5-

toluenesulfonamidocarboxy)benzyl|indazoline, 5-amino-1-|2-methoxy-4-(o-toluylsulfonamidocarboxy)benzyl|indazoline are obtained as a result! reduction of 5-nitro-1-(2-methoxy-4-(o-toluylsulfonamidocarboxy)benzene|indazoline. IN NMR ЮМ5О-а6): (77.87 (0,

IN, 102 and 7.7 Hz), 7.73 (in, 1), 7.50 (5, 1H), 7.35-7.14 (t, 5), 6.78 (FIN, 1 x 1 ,8

Hz), 6.75 (in, IN), 6.53 (y, IN, 4 - 8.2 Gyi), 5.44 (5, 2H), 3.82 (5, ZNU, 2.50 (5 , ZN). 7.2.48 Prototyping of 8-amino-4H-imidazoi2,1- "ZHI, ReVio uv Me in i zro a s), 4)-benzoxazi! ore tvo Oma in M z

LVS well Mo ele 577 MO; 7.3 Synthesis of 2,4-pyrimidinediamines A large number of 2,4-pyrimidinediamines according to the present invention were synthesized from the above starting materials and intermediate compounds, as well as other commercially available reagents. Conditions suitable for the synthesis of M2,M4-bs-substituted-2,4-pyrmidineliamine compounds (conditions of the "general ZMAg" reaction - aromatic nucleophilic substitution reaction) are described with examples

M2,M4-bis(4-ethoxyphenyl)-2,4-pyrimidinediamine (8926069) and M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (K921218). Conditions suitable for the synthesis of asymmetric M2,M4-disubstituted -2,4-pyrimidinediamines are described on the example of MA-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine ( K926210), 7.34 M2,M4-bis(4-ethoxyphenyl)-2,4- 4-pyrimidinediamine (K926069) ethoxyaniline ( 0.034 g, 0.025 mmol) and heated in a hermetically sealed tube at a temperature of 70-80°67 for 74 hours. After cooling, the reaction products are dissolved in water (10 ml), acidified with a solution of 214 NCI, and the resulting solid fraction is filtered, washed with water and dried to form M2,M4-bis(4-ethoxyphenyl)-2,4-pyrimidinediamine (K926069). IN NMR (CO300u: 0 7.63 (a, 1NU, 7.45 (y, 2Н), 4-2 9 Hz), 7.39 (0, 2Н, У- 9.3 Hn), 6.95 ( 4, 2H. 1- 6.9 Hz), 6.87 (y, 2H, 1-x: 8.7 Hz), 6.23 (y, IN, 12 7.2 Hz), 2.04 (t , 4H), 1.38 (t, 6H);

LC/MS: retention time: 25.91 minutes; purity: 99.5; MC (mass/charge): 351 (MN). c 7.32 M2um4-bis(3-tihydroxyphenyl)-3-fluoro-2,4- | Sums of 2,4-dichloro-5-fluoropyrimidine (0.0167 g, 0.1 mmol) and 3-aminophenol pyrimidinediamine (K921218) 9.033 g, 0.3 mmol) in MeOH: HO (1.8:0.2 ml by volume) is shaken in (o) a hermetically sealed tube at a temperature of 1000 for 24 hours (or at a temperature of 800C for 3 days), cooled to room temperature, dissolved in water (15 ml) and acidified with a solution of 2M HC (pHO»2) . After saturation with sodium chloride, the mixture is extracted with ethyl acetate (3 x 20 (Che) ml) and dried over anhydrous sodium sulfate, and the solvent is removed.

The resulting residue is filtered through a silica gel pad (He density) of cells -200-400 met), using SNOSI2 -21 »1090 solution of MeOH in

SNCI2 with the formation of the necessary M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (K921218). With a sufficiently large scale of the reaction, the solid or fraction of the product obtained can be separated by filtration. IN

LMR (SOSIZ): 7.73 (0, 1, 2: 5.1 Si), 7.12-6.90 (t. 6H), 6.64 (dp, 1H, 1- 1.8 and sem 8 ,1 Hz), 6.53 (yes, IN, 3-- 1.2 and 5.7 Gy); LC/MS: retention time: 16.12 minutes; purity: 10095; MS (mass/charge): 313 (MNK). so 7.33 M2,MA-bis(4-methoxyphenyl)-5-fluoro-2,4- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (K926017) pyrimidinediamine, 142, M4-bis(4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-methoxyaniline.

IN NMR (SPZOI): 0 7.67 (4, 1, 2- 4.8 y), 7.43 (8, 2H, 92 93 Hyd), 7.67 (4, 2H, Y- 8.7 Gy ), 6.87 (a, 2H, 1-5 9.6 Hz), 6.83 (y, 2H, /e 8.7 Hz), 3.83 (5, ЗН), 3.81х8, ЗН) ; "

LC/MS: retention time: 22.53 minutes; purity: 10005; MS (mass/charge); 341. fluoro-2,4-pyrimidinediamine, M2,M4-bis(3-fluoro-4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine (K926018) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and n z» of 3-phthor-4-trifluoromethylaniline. IN NMR (SOSIZU; GI 801 (4, 1, 3: 3 Ho), 7.77 (t, I ZNU, 7.61 (F,1H, 7: 4, 2 and Z Hn), 7.200, 1H, 8.7 Gy), 7.12 (6 IN, 12: 9.3 Hyd), 6.95 (5,

IN), 6.82 (5, IN 9 YAM (SOSI3): 2 --17505 (85, ZE), -17517 (8, ZE), "17525 (8, E), - 17537 (5, KE), -46835 (5, 1E); LC/MS: retention time: 32.39 minutes; purity: 9595, MS (mass/charge): 453 (MNE). (ee) 7.3.5 M2,Ma-bis(3, 4- Similarly to the preparation of M2,M4-bis(3-tihydroxyphenyl)-5-fluoro-2,4-tetrafluoroethylenedioxyphenyl)-5-fluoro-pyrimidinediamine, M2,M4-bis(3,4-tetrafluoroethylenedioxyphenyl)-5-fluoro-2 ,4-ka 2,4-pyrimidinediamine (926037) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3,4-tetrafluoroethylenedioxyaniline. 1H NMR (SOSISU: CI 8.01 (6, IN, 7- 3 ,0 Gy), 7.714, 1.15 2.4 Hz), 7.70 (IN, 4, 252.4 Gy), 7.18 (409, 2H, 12 2.4 and 6 Hz), 7.07 (4, -y 2H, 1.8 Ga), 7.00 (IN, B5), 6.81 (b, 1H, le 2.7 Hz); 19E NMR (SSZ): -26029 (zero,

BE), -46791 (8, C5-E); LC/MS: retention time: 38.20 minutes; purity: 85925;

He MS (mass/charge: 541 (MNE), (42) ko 60 b5

7.3.6 142,M4-bis(z-trifluoromethoxyphenyl)-5- Similar to the preparation of 42,144-bis(3-hydroxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (K926038) pyrimidinediamine, M2,M4 -bis(3-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-trifluoromethoxyaniline. IN NMR (SUOSIZ); y7 8.03 (59, 1), 7.62 (B, 2H), 7.48 (Ba, 1H), 7.396 1H, 2-8, Gi), 7.34 (t, IN), 7.29 (pH, 3-5 7.5 Hz), 7-01 (t, 2H), 6.58 (t, 2H); I9E NMR (SOSIZ): "16447 (5, ZR), -16459 (5, ZE), -46738 (5, 12); RH/MIS: retention time: 33.77 minutes; purity: 9395; MC (mass/charge): 449 (MN-K). 73 2, Ma-bisg4-chloro-3- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-z-fluoro-2,4-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine, M2,M4-bis (4-chloro-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine (4926039) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-chloro-3-trifluoromethylaniline. IN NMR (SOSIS): 0 8.05 (b, 1), 7.89 (va, 1H), 7.77 (ai, 1H, 3- 2.4 and 9 Hz), 7.65 (4d, IN , 1: 2.4 and 8.7 Gy), 7.49 (4, 1-8.1 Hz), 7.40 70 (4.1H, 226.2 Hy, 7.03 (5, 19), 6, 91 (5, IN); 192 NMR (SOSIZ): GI -- 17864 (5, ZEU, - 17894 (5, ZE), -46550 (5, 1E); LC/MS: retention time: 38.81 minutes; purity: 7595; MS (mass/charge): 485 (MH). 7.3.8 M2,Ma-bis(3-ethoxyphenyl)-5-fluoro-2,4- Similar to preparation 42, M4-bis(3-hydroxyphenyl) -5-fluoro-2,84- pyrimidinediamine (5926064) pyrimidinediamine, М2,М4-б15(3-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3 -stosignilin.

IN NMR (SOZO): P 7.96 (IN, d, 2-48 Hz), 7.22 (t, 6H), 7.07 (5, 18, 2 1.8 G in), 6.95 ( 4, 1H, ze 1.2 and 7.2 Hz), 6.77 (t, 2), 3.88 "4, 4H, 226.3 Gy), 1.33 (scho i, 6H, 1-63 Hz; I9E YAM? (SOSIZ): "46175; RH/MO: retention time: 26.86 minutes; purity: 9755; MS (mass/charge): 369 (MNE). 17.39 M2,M4-ZkuZ-tihydroxy-4 -methoxyphenyl)-5- | Similarly to the preparation of M2,х4-bis(3-hydroxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (К926339) pyrimidinediamine, M2,М4-bis(3-hydroxy-4-methoxyphenyl)-5- fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-tihydroxy-4-methoxyaniline. IN NMR (SOSOBI: (17.82 (y, NI 4 Gy), 7.18 (yv, 2H), 6.95 (t, 2NI), 6.83 (t, 2A1) 3.93 (5, 6H); LC/MS: retention time: 16.63 minutes; purity: 97 95; MS (mass/charge): 373 (MNE). 73.10 M2,M4-bk4-ethoxycarbonylamino-3" Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4 - hydroxyphenyl)-5-Fluoro-2,4-pyrimindiamine, M2,M4-615(4 ethoxycarbonylamino-3-hydroxyphenyl)-5-fluoro-2,4-nyrimidinediamine (KU26340) tyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro -5-fluoropyrimidine and 4-ethoxycarbonylamino-3-hydroxyaniline.IN NMR (SOSO): 17.86, 1H 7-4

Gy), 7.67 (t, 2H), 7.20 (did, 1H, 12 8 Hz, 14.1 Hn), 7.13 (y, 1H), 6.90 (t, 2H), 4, 2 (t, 4H), 1.32 (pi, 6H); LC/MS: retention time: 20.92 minutes; purity: 98 55; everything

MC (mass/charge): 487 (MN). o 7341 M2,M4-bis(-3-hydroxy-4-methylphenyl)-3- | Similarly to the preparation of M2,M4-bio(3-hydroxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine, pyrimidinediamine, M2M4-bis(-3-hydroxy-4-methiaphenyl)-5-fluoro-2, 4- (8926341) pyrimidinediami" are obtained as a result of the reaction of 2,4-diphor-5-fluoropyrimidine and

3-tihydroxy-4-methylaniline. 1H NMR (SOZOB): 117.83 (y, 1H 72 4 Hz), 7.11 (t, 48), 6.81 (t, 2H), 2.19 (pu, 6H); РЧ/МС: duration of retention; 20.69 minutes; purity: (se) 98 95; MC (mass/charge): 341 (MN). 7.3.2 М2,МА-bis|4-(2-DA) for the preparation of М2,М4-bis(3-hydroxyphenyl)-5-fluoro-2,4- (22) methoxyethyleneoxy)phenyl-5-fluoro--2,4 - pyrimidinediamine, M2,M4-bis|4-42-methoxyethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediamine (5926342) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and or 4-(2- methoxyethyloxy)aniline. IN NMR (SOZOUU 117.89 (4, 1 7-4 Gy), 7.54 (ai, 2H, 126.8 and 2.7 y), 7.38 aa, UN, 1- 6.8 and 2.7 Hz) , 6.87 (09, 2H, 1- 6.8 and 2.7 Hz), se 6.82 (44, 2H, )-: 6.8 and 2.7 Hz) 4.6 (t, 48), 4 .11 (t, 4H), 3.35 (t, 6H); LC/MS: retention time: 21.76 minutes; purity: 97th; MS (mass/charge): 429 (MNE). so 7.3.13 M2,M4-bis(dihydrobenzofuran-5-yl)-5- Similar to the preparation of M2,h4-Bis(3-hydroxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine, 2 ,M4-bis(ditihydrobenzofuran-5-1l)-5-fluoro-2,4- (8909237) pyrimidinediamindismine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 5-amino-2,3-dihydrobenzofuran. TYA NMR (SO3OYU): 117.99 (y, 1NI-4G), 7.22 (t, 4NU, 6.81 (t, 2), 4.55 (tv, 48, 3.22 (t, 4H) ; LC/MS: "retention time: 23.80 minutes; purity: 98 95; MS (mass/charge): 438 (Mn. 7.3.14 M2,M4-bis(3-methoxyphenyl)-5-fluoro-2, 4- Similar to the preparation of M2, Ma-bis(3-hydroxyphenyl)-5-fluoro-2,4- -o pyrimidinediamine (KU26065) pyrimidinediamine, M2, Ma-bis(3-methoxyphenyl)-5-fluoro-2,4- pyrimidinediamine c is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-methoxyaniline.

IN NMR (SOZOD: 0 7.96 (0, 1H, 1- 5.4 Hz), 7.24 (t, 6H), 7.06 (, IN, 1- 2.4 Hz), n z» 7 .00, 1H, 15 1.2 Hz), 6.79 (t, IN), 3.72 (v, ЗН), 3.79 (5, ЗН); I9E NMR "SOZOB"): p. 21 -46112; LC/MS: incubation time: 23.46 minutes; purity: 9995; MS (mass/charge): 341 (MNK). 7.3.15 1M2х4-bisi4-(M,M-dimethylamino)phenyl- | Similar to the preparation of M2,44-bis(3-hydroxyphenyl)-5-fluoro-2,4-5-fluoro-2,4-pyrimidinediamine (8926086) | pyrimidinediamine, M2,M4-bis/4-(M,M-dimethylamino)phenyl-5-fluoro-2,4-(ee)pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-M, M-dimethylaniline. IN NMR (SOSIZ); 7.84 (4, 1, 2: 3.6 Hz), 7.3 (y, 2H, 1-t 8.7 Hz), 7.34 (6, 2H, 78.7 Hn), 7.25 (v, IN ), 6.73 (t, 48), 65518, 1H), 2.95 (5, 6H), 2.90 (5, 6H)U; 192 NMR (SOSISU: -47770; RH/MS: retention time: 12.48 - minutes; purity: 9995; MS (mass/charge): 367 (MN.K), 7.3.16 MO, Mma-bib(3, 4 ethylenedioxyphenyl)-5- Analogously to the preparation of M2,M4.bis(3-hydroxyphenyl)-5-fluoro-2.4- "with 50 fluoro-72,4-pyrimidinediamine (926109) pyrimidinediamine, M2,M4-bis(3,4- ethylenedioxyphenyl)-5-fluoro-2.4-pyrimidinediamine 42) ko 60 b5 fluoro-2.4-pyrimidinediamine (К926109) is obtained as a result of the reaction of 2,4-dichloro-z-fluoropyrimidine and 3,4-ethylenedioxyniline. IN NMR(SOCI3): 7.88 (4, 1H, 7: 3.6 Gy), 7.23 (8, 1H, 3-23

Gnu 7.15 (4, 1H,2- 2.4 Gy), 7.00 (440, IN, 3-Z and 8.1 Hn), 6.98 (y, 1H, 1-Z and 8 Hz) , 6.83 (4, 1H, 1-8.7 Hz), 6.81 (d, IN, I- 8.7 Hz), 6.7(5, 18), 6.58 (5, 1H) , 4.23 (t, 4H), 4 oKt, 4H); ISE NMR (SOSIZ); With -47445; РЧ/МС: duration of retention; 21.81 minutes; purity: 9605; MC (mass/charge): 397 (Mn. 7.3.17 M2,M4-bis(3,4-dimethoxyphenyl)-5-fluoro- Analogously to the preparation of IM2,MA-bis(3-hydroxyphenyl)-5-fluoro-2, 4- 2,4-pyrimidinediamine (K926110) pyrimidinediamine, M2,M4-bis(3,4-demethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-2-fluoropyrimidine and 3, 4- dimethoxyaniline. IN NMR (SOSIS): Si 7.90 (d, IN, A- 1.8 Hz), 7.13 (a, 2H, 1- 4.8

Gy), 7.08 (3, IN, 2-- 8.7 Go), 6.94 (0, 2H, 3- 19.5 Gy), 6.81 (4, 1H, 7- 8.7 Hz ), 6.76 (and,

TN,1- 8.7 Go), 6.70 (5, 180), 3.87 (5, ZN), 3.84 45, Z), 3.74 (5, ZN), 3.71 (5 , ZNU; 19E

NMR (SOS): 0 47433; RHLMS: retention time: 19.64 minutes; purity: 9595; MC (mass/charge): 401 (MN). 7.3418 M2,M4-bis4-(M-morpholine)phenyl|-5- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (К926114) pyrimidinediamine, M2,44-bis4-M-morpholinyl)phenyl|-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-M-morpholinylaniline. IN NMR (COSO): GP 7.80 (5, 18), 7.78 (5, IN, partially substituted), 7.76 (55, 1Н, partially substituted), 7.53 (4, 2Н, /- 8.1 Hz), 7.39 (y, 2H, 159 Gy), 6.93 (y, 2H, 7-8.7 Gy), 6.86 (Ba, 2, 3.84 (t, 8H) . 7.3119 M, M4-bis(4-chlorophenyl)-5-fluoro-2,4- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (KO26206) nirimidinediamine, M2,44 -bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-chloroaniline. . ... bis(3-chlorophenyl)-5-fluoro-2,4- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4- pyrimidinediamine (2926209) pyrimidinediamine, M2,M4-bis(3- chlorophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-chloroaniline. IN NMR

ISO305): 15 8.08 (d, 1H, 2: 5.4 Hz), 7.70 (i, IN, 75 1.8 Gy), 7.57 (B IN, 121.2 Go), 7, 54 t, 1H), 7.35 (t, 4), 7.28 (6 1H, 7- 1.8 Gu, 7.24 (t, ENU, 7.22 (B 1H, 121.8

Gy); 192 YM (SOZOB): -43631; LC/MS: retention time: 28.99 minutes; sem purity: 9990; MS (massage/charge): 349 (M g). 7 - o 7.3.21 m2,M4-bis(4-tert-bButylphenyl)-5-fluoro- Similarly to the preparation of M2,Ma-bis(3-hydroxyphenyl)-5-fluoro-2,4- 2,4-pyrimidinedismin ( K9262272) of pyrimidinediamine, M2,M4-bis(4-tert-butylphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-tert-butylaniline. IN NMR (SOSIS): 7 7.77 (4, 1H,, 72: 3.9 Gy), 7.47 (4, 2H, 1-9), 7.38 (t, 4A1U, 7.39 (0 , 2H, 12: 8.7 Hz), 1.34 (5, 9NU, 1.32 (5, ЗН); LC/MS: retention time: 34.09 minutes; purity: 9395; ME: 393 (MN) . (se) 7.3.77 m2,M4-bis(3-chloro-4-fluorophenyl)-5-fluoro- | Analogous to the formula M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4- 2.4- pyrimidinediamine (4926223) pyrimidinediamine, M2,M4-bis(3Z-chloro-4-fluorophenyl)-5-fluoro-7,4-pyrimidinediamine b" is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-chloro- 4-fluoroaniline. IN NMR (SOSIZ 4 SRZOYUI: From 7.81 (8, IN, 7.60 (t, 18), 7.58 (t, che: 1NU, 7.38 (t, IN), 7, 19 (p, 1H), 7.0 (ho, 2H); RH/MS: retention time: 28.98 minutes; purity: 9795; MS (mass/charge): 385 (M). s 7.3.273 MO, M4-bis(4-fluorophenia)-5-fluoro-2,4- Similar to the preparation of M2,Ma-bis(3-hydroxyphenyl)-5-fluoro-2,4- pyrimidinediamine (926224) pyrimidinediamine, M2.M4-bis( 4-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-fluoroaniline.

IN NMR (SOSIZ): O 8.79 (4, 2H, 7: 5.4 Hz), 7.40 (t, 2H), 7.30 (t, 2), 6.90 (t,

ANU 19NMR(SOSIZU: -32425 (85, 1E), -32940 (5, 1E), 445525 (5, 1KE); RF/MS: retention time: 23.53 minutes; purity: 10095; MS (mass/mass) : 317 (MH B). 7.3.2A M2,M4-bis(4-methniphenyl)-5-fluoro-2,4- Similar to the preparation of M2,h4-bis(3-hydroxyphenyl)-5-fluoro-2,4- « pyrimidinediamine (5926225) pyrimidinediamine, M2,M4-bis(4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-methylaniline.

IN NMR (SOSIVKH 9 7.73 (0, NU, 7 4.2 Hz), 7.43 (0, 2H, le 8.1 Gii), 7.36 (0, 2H, 1 - s 8.4 Hz ), 7.14 (4, 2H, 1-84 Hz), 7.10 (4, 2H, 7e 8.1 Hz), 2.39 (5, ZNU, 2.35 (5, ZNU;

LC/MS: retention time: 25.81 minutes; purity: 99.6590; MS (mass/charge): h 309 (МН.Ю. шчи » 7.3.25 2, ma-bisr(4- Avaporically prepared M2,M4-bis(3-hydroxyphenia)-5-fluoro-2,4- methoxycarbonylmethyleneoxy) phenyl|-5-pyrimidinediamine, M2,M4-bis|(4-methoxycarbonylmethyleneoxy)phenyl|-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (K926240) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro- 5-fluoropyrimidine and ethyl 4-amicophenoxyacetate. IN NMR(SPZOB): I 7.8 (Bb5, 18), 7.50 (0, 2H, 1- 93

Hz), 7.32 (60, 2H, 2- 8.41 Hz), 6.88 (t, 4H), 4.72 (v, 2H), 4.70 (5, 2H), 3.79 (5, ZN), at 3.78 (in, ZN); 19E NMR KSOSIS): -47570; LC/MS: retention time: 21.17 minutes; purity: 9595; MS (mass/charge): 457 (MNK). ko 7.3.26 (CH-M2,M4-bis|4-methoxycarbonyl (a- Analogously to the preparation of M2,Ma-bis(3-hydroxyphenyl)-5-fluoro-2,4-methyl)methyleneoxyphenyl|-z-"fluoro- 2,4-pyrimidinediamine, SK)-M2,M4-bis/!4-methoxycarbonyl I -methylumethyleneoxyphenyl|- shk pyrimidinediamine (8926254. 5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5- (Ce) (42) co 60 b5 pyrimidinediamine (K926254) fluoropyrimidan and (C)-ethyl 2-(4-aminophenoxy)propionate 1H NMR (SOS): 7.89 (05, IN), 7.48 (ai, 2H, /- 2.4 and 6.9 Hyd), 7.40 (ai, 2H, /- 1.8 and 6.9 Hyd), 6.85 (t,

AN), 6.76 (5, IN), 6.63 (5, IN), 4.75 (peh, 25, /» 6.3 Hz), 3.77 (z, ZNU, 3.76 (in, ZN ), 1.62 (6 OH, 1" 7.5 Hz); LC/MS: retention time: 23.76 minutes; purity: 9795,

MS (mass/charge): 485 (MNK), 73.27 mo, ma-bisc3- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4- methoxycarboniamethyleneoxy)phenyl|-5-pyrimidinediamine, 142 . IN NMR(SOSIZ): 0 7.964, 1H, 25 2.4 Hz), 7.71 (5

IN, 32 2.4 Hz), 7.44 (t, 2H), 7.21 (pu, ZN), 6.96 (44, IN, 12 1.2 and 7.8 Gy), 6.86 ( y, 1H, 1-3 Hz), 6.53 (t, IN), 4.64 (5, 2H), 4.60 (5, 2H), 3.79 (8, NU; RHLMS: duration of retention: 21.72 minutes; purity: 8795; MS (mass/mass): 457 (Mn.Yu). 7.3.28 M2,M4-bis(3-acetnloxyphenyl)-5-fluoro- Analogously to the preparation of M2,M4-bis(Z -hydroxyphenyl)-5-fluoro-2,4-2,4-pyrimidinediamine (K926387) pyrimidinediamine, M2,M4-bis|(3-acetoxyphenyl|-5-fluoro-2,4-pyrimidinediamine) is obtained as a result of the reaction of 2,4 -dichloro-5-fluoropyrimidine and 3-acetoxyaniline. Alternatively, IR2,M4-bis|(3-anethoxyphenyl|-5-fluoro-2,A-pyrimidinediamine can be obtained by cetylation of M2,M4-bis(3-hydroxyphenyl )-5-fluoro-7,4-pyrimidineliamine with acetylchloryl in the presence of pyridine and CH2CI2. 32 (5, ZNU, 2.28 (5, ZN); RH/MS: retention time: 22.14 tiv; purity: 10095;

MS (masg/charge): 397 (MN). 7.3.29 2, m4-bis(3-benzyloxyphenyl)-5-fluoro- Analogous to the preparation of M2,44-bis(3-hydroxyphenyl)-5-fluoro-2,4- 2,4-pyrimidinediamine (K926394) pyrimidinediamine, M2 ,MA-bis(3-benzyloxyphenyl)-5-fluoro-2,4-pyrimidineliamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-benzyloxyaniline. NMR (SOSIZ): C17.98 (05, 1H), 7.42-6.99 (t, 16H), 6.75 (d, 1H, 1-2.4 Gy), 6.71 (in , 1), 6.60 (46, IN, 3-- 2.4 and 8.4 Gy), 6.32 (t, 18), 4.97 (5, 2H» 4.94 (5, 2H); /MS: retention time: 32.56 minutes; purity: 9890; MS (mass/mass): 493 (MNK. 7.3.30 M2,MA-bis(2-phenylphenyl)-5-fluoro-2,4- Similar to the preparation M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (K926398) of pyrimidinediamine, M2M4-bis(2-phenylphenyl|-5-fluoro-2,4-pyrimidindiamine) is obtained as a result of the reaction of 2,4 -dichloro-5-fluoropyrimidine and 2-phenylaniline. 1H NMR (SOSISU: (18.35 (t, IN), 8.0 (5, NU, 7.85 (5, 1), 7.45-7Ю ( t, 18);

LC/MS: retention time: 30.29 minutes; purity: 6895; MC (mass/charge): 433 (MN). c 7.3.31 (8926404) M2, MA-bis(2-phenylphenyl)-5- Similar to the preparation of 5-fluoro-h2,M4-bis(3-tihydroxyphenyl)-2,4-o methyl-2,4-pyrimidineliamine pyrimidinediamine , M2, M4-bis(2-phenylphenyl)-5-methyl-2,4-pyrimidinediamine is obtained as a result of resection of 2-aminobiphenyl and 2,4-dichloro-5-methylpyrimidine.

LC/MS: retention time: 30.47 minutes; purity: 9124; MS (mass/charge): 429 (Mn. 7.3.372 M2,Ma-bis(4-methoxy-3-phenyl)phenyl-5- | Similar to the preparation of M2,M4-bis(3-tihydroxyphenyl)-5-fluoro- 2,4-iso fluoro-2,4-trimidinediamine (К926399) of pyrimidinediamine, 2, M4-bis(4-methoxy-3-phenyl)phenyl|-5-fluoro-7,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro -5-fluoropyrimidine te Me, 4-methoxy-3-phenylaniline.IN NMR (SOZOI): CI 7.83 (4, IN, 1-49 Gy), 7.57 (Bii, 1H.1-8.7 Hz ), 7.48 (0, 1H, 152.7 Hz), 7.47-7.22 (t, 12H), 6.85 (y, 18, 7-5 8.7 Ha), h- 5, 78 (90, 1H, 9.3 Gy), 3.72 (5, ZNO), 3.69 (5, ZN); LC/MS: retention time: 29.97 minutes; purity: 9225; MS (mass/charge) : 493 (MNK). c 7.3.33 M2,MA-bisc(2-methoxy-5-phenylphenyl|-5- Analogously to the test M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4- fluoro- 2,4-pyrimidinediamine (K926400) pyrimidinediamine, 2, Ma-bis|(2-methoxy-5-phenyl)phenyl|-5-fluoro-2,4-(ee) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro- of 5-fluoropyrimidine and 2-methoxy-5-phenananiline. IN NMR (SOSO): C 8.03 (y, 1H, 7- 6.6 Hz), 7.76 (y, IN, 122.4 Hz 7.28-7.10 (t, 13H)), 7.07 (6, IN, 32: 9 GP), 7.01 (4, 1H, 1- 8.1 Hn), 3.91 (5,

ZN), 3.86 (5, ZN); RH/MS; retention time: 18.53 minutes; purity: 9695; MS (mass/charge): MNK). « 7.3.34 m2,M4-bis1(2-methoxy-5-methyl-4- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-phenyl)phenyl-5-fluoro-2 ,4-pyrimidinediamine, M2,M4-bio|(2-methoxy-5-methyl-4-phenyl)phenia|-5-fluoro-2,4- with pyrimidinediamine (K926401) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro -5-fluoropyrimidine and c 2-methoxy-5-methyl-4-phenylaniline. IN NMR (CO3OB): HO 8.00 (4, IN, 1-48 Gy), 7.73 (in, 1), 7.66 (8, 1Н), 7.43-7.24 (t, 9Н), 6.91 (5, 1H), 6.82 (5, IN), 3.86 (5. ZN), m » 3.85 (z, ZN), 2.14 (5, ZN), 1.99 (5, ZNU, RH/MS: retention time: 19.98 minutes; higher purity: 9995; MS (mass/charge): 521 (MNK). 7.3.45 M2,Mm4-bis((2-methyl-5- phenyl)phenyl|-5- Similar to the preparation of M2,Ma4-bis(3-hydroxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (K926402) pyrimidinediamine, Ma, ma-bis|(o-methyl -5-phenylphenyl|-5-fluoro-2,4-pyrimidineliamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 2-methyl-5-(ee)phenylaniline. IN NMR (SPZOBU: 0 7.84 (Ba, 1), 7.51-7.20 (t, 16), 2.30 (5, ZN), 2.24 (5, ZNU; RH/MS: retention time: 18.57 minutes; purity: 8790; MS co (mass/charge): 461 (MNK). 7.3.36 142,M4-bis|(3-phenyl)phenyl)-5-fluoro-2,4- Similar to the preparation of 142,M4-bis(3-hydroxyphenyl)- 5-fluoro-2,4- rac pyrimidinediamine (K926403) pyrimidinediamine, M2,M4-bis((3-phenyl)phenyl|-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichlor or-5-fluoropyrimidine and 3-phenylaniline. "se 20 IN'NMR(SOZOI; 11 8.02 (4, 1H, 72 5.1 Hz), 7.82 (, IN, 12 1.5 Gy), 7.67 0 IN, ze 42) ko 60 b5

TYA g), 7.58(44, IN, 7 1.2 and 7.2 Ha), 7.42-7.24 (t, 1583; RH/MS: retention time: 32.06 minutes; purity: 9495 ; MS (mass/charge): 433 (MH). 73.37 Mm2,ma-bis(4-hydroxyphenia)-3-fluoro-2,4- | Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro -2,4-pyrimidinediamine (К926405) pyrimidinediamine, M2,M4-bis(4-hydroxyphenyl|-5-fluoro-2,4-pyrimidinediamine) is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-anethoxyaniline. After after completion of the reaction, it was observed that the acetoxy group was hydrolyzed, with the formation of M2,M4-bis(4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine instead of the corresponding acetate derivative compound. IN NMR (СО3О00): 2 7.74 ( b, IN, 1- 5.6 Gy), 7.43 (4d, 2H, 1: 2.1 and 6.6 Hz), 7.28 (j, 2H, 1 2.4 and 6.3 Hz) , 6.74 (40, 2H, 12.4 and 6.3 Gy), 6.66 (ii, 2H, 1:24 and 7.2 Hz); 19E

NMR (SrzOB): -48116 (y, 1E); PH/MS: duration of retention: 16.15 tip; purity: 10095; MS (mass/charge): PPE (INN). 7.3.38 MMA -bis(4-hydroxy-3-methylphenyl)-3- | Similarly to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (K926469) pyrimidinediamine, M2,M4-bis(4-hydroxy-3-methylphenyl|-5- fluoro-2,4-pyrimidineliamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-tihydroxy-3-methylaniline. IN NMR (SOZORU: 2 7.64 (0, 1Н, 323.6 Hz) 7, 11 (6

KhN, 1-9 Gy), 6.70-6.45 (t, 48), 2.15 (in, ZN), 2.09 (5, ZN); 19E NMR (SOZOYU): - 46278; РЧ/ЛМС: length of stay; 15.53; purity: 8495; MS (mass/charge): 341 (Mn. 715 7.3.39 M2,MA-bisi4-(tert) Analogously to the preparation of M2,44-bis(z-hydroxyphenyl)-5-fluoro-7,4-butoxycarbonylmethyleneoxy)phenyl|- 5-pyrimidinediamine, M2,MA-bis(4-(tert-butoxycarbonylmethyleneoxy)phenyl|-5-fluoro- fluoro-2,4-pyrimidinediamine (К926574); 2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro- of 5-fluoropyrimidine and tert-butene-4-aminophenoxyacetate.IN NMR (SOSIS): HI 7.88 (in, IN), 7.48 (4, 2H. 1-84 Gy), 7.404, 2H, 1- 8.7 g ), 6.86 (t, AN), 4.52 (5, 2H), 4.48 (v, 2H), 1.49 (5,

UNI), 1.48 (5, 9H); LC/MS: retention time: 28.48 minutes; purity: 9599; MS (mass/charge: 541 (MNK). 7.3.40 M2,M4-bisyndol-5-yl)-5-fluoro-2,4- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro -2,4-pyrimidinediamine (K926582) pyrimidinediamine, IM2,M4-bis(indole-5-1l)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 5-aminoindole . LC/MS: retention time: 20.26 minutes; purity: 9995; MC (mass/charge): 359 (MN). 7.3.41 M2,M4-bis(4-cyanomethylphenyl)-5- Similar to the preparation of M2,IM4-bis(3-hydroxyphenyl)-5-stoxycarbonyl-7,4-ethoxycarbonyl-2,4-pyrimidinediamine pyrimidinediamine, M2,Ma- bis(4-cyclomethylphenyl)-5-ethoxycarbonyl-2,4- (К926319) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-sem ethoxycarbonylpyrimidine and 4-cyanomethylaniline. IN NMR (YUM50-46): 128.72 (5, 1Н), 7.64 (t, 4Н). 7.32 (a, 2H, 12 8.7 Hyd, 7.21 (I, 21, 1- 8.4 Hz), 4.3 (a, 2H, I- 70 Ge)

Gy), 3.97 (5, 2H,), 3.59 (5, 2NU, 1.32 (ZN, 1-7 Gy); LC/MS: retention time: 30.83 minutes; purity: 90 95; MS ( mass/charge): 413 (MH). 7.3.42 M2,ma-bis(3-indazol-6-yl)-5- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-stoxycarbonyl-2,4 - ethoxycarbonyl-2,4-pyrimidinedigmine of pyrimidinediamine, IM2,4-bis(b-indazolyl)-5-ethoxycarbonyl-?,4-pyrimidinediamine (se) (5926320) are obtained as a result of the reaction of 2,4-dichloro-5-ethoxycarbonylpyrimidine and 6-aminoindazole. IN NMR (0M50-46): (18.76 (8, 1H), 7.73(4, 2H 1 8.8), 7.54 (t, F "NU, 7.36 (y . MS (mass/charge): 415 (MNK). 7.3.AZ MO Ma-biv(3ndazolo? chl 3 Analogously to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4- - ethoxycarbonyl-2, 4-pyrimidinediamine of pyrimidineliamine, M2M4-bis(7-indazolyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine (8926321) is obtained as a result of the reaction of 2,4-dichloro-5-ethoxycarbonylpyrimidine and 7-aminoin Dazol IN NMR (PM50-y6): 28.70 (5, 1H), 7.54 (0, 2H 72: 8.4 Gy), 7.37 (t,

NU 43 (4, 2H, 1: 7, Hu, 1.33 (ZN, 2: 7 Gy), RH/MS: retention time: 23.61 (ee) minutes; purity: 94 95; MS (mass/charge ): 415 (MNK). 7-3.44 M2,M4-bisib-401,4-benzoxazin-Z-onyl)|-2- | Analogously to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-ethoxycarbonyl-2,4-ethoxycarbonyl-2,4-pyrimidinediamine pyrimidinediamine, M2,M4-615(16-(1,4-benzoxazin-3-onyl) )-5-ethoxycarbonyl-2,4- (8926325) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-ethoxycarbonylpyrcmidine and the compound b-amino-1,4-benzoxazin-3-one. IN NMR (pPM5O-46): H18.66 (5, NNU, 7.21 (ad, 2H 1 8.8 and 1e- 2.2 Hz), 6.89 (0, 2H 1- 8.4 GIV ), 4.54 (5, 2NI) 4.49 (5, 2H) 4.3 (9, 2H, 1--7.0 Hn), 1.33 (ZN, 1I-7 Gy); LC/MS : - retention time: 23.08 minutes; purity: 88 90; MS (mass/charge): 477 (Mn.Yu). c 7.3.A5 M2,M4-bis(4- Similar to the preparation of M2,M4-bis(3 -hydroxyphenyl)-3-ethoxycarbonyl-2,4-h ethoxycarbonylmethyleneaminophenyl)-5-pyrimidinediamine, M2,M4-bis(4-ethoxycarbonylaminophenyl)-5-ethoxycarbonyl-2,4- and R. ethoxycarbonyl-2,4-pyrimidinediamine pyrimidinediamine obtained as a result of the reaction of 2,2-dichloro-5- (K926331) stooxycarbonylpyrimidine and 4-ethoxycarbonylmethyleneaminoaniline. 1H NMR (SOCI3): 218.72 (5, NU, 7.79 (0, 2H 1e 8.8 Hyd), 7 ,28 (d, 2H 1: 8.4 Gy), 7.05 (y, 2H, 12 5.4 Hz) 6.82 (0, 2H 3- 8.4 Gy) 4.5 (t, 4), 4 .23 (tp, 6H) 1.53 (t, 9H)U; LC/MS: retention time: 18.08 minutes; purity: 8595; MS (mass/charge): 537 (MN). (ee) 7.3.A6 M2 ,Ma-bis(4-ethoxyphenyl)-6- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4 - methoxycarbonyl-2,4-pyrimidinediamine of pyrimidinediamine, M2,M4-bis(4-stoxyphenyl)-6-methoxycarbonyl-2,4- co (8926058) pyrimidinediamine is restrained as a result of the reaction of 2,4-dichloro-6-methoxycarbonityrymidine and 4- ethoxyanilim. 1H NMR (SOSISU HI 7.42 (b5, 18), - 7.35 (va, AN), 6.85 (65, 1), 6.75 (64, AN), 3.97 (o, 4H, 1-48 Hz), 3.92 (5, ZNU, 1.36 (b 6H, le 6.3 Hz); RH/MIS: retention time: 27.47 minutes; purity: 972; MS (mass/charge) : 409 (MN). (Se) 42) ko 60 b5

7-3.47 M2,M4-bi(4-ethoxyphenyl)-5-methyl-2,4- Similar to the preparation of M2,Ma-bis(3-hydroxyphenia)-5-fluoro-2,4-pyrimidinediamine (2926068) pyrimidinediamine, M2 ,M4-bis(4-ethoxyphenyl)-5-methyl-2,4-pyrimidineliamine is obtained as a result of the reaction of 2,4-dichloro-5-methylpyrimidine and 4-ethoxyaniline.

IN NMR(SOZOB): 2 7.55 (5, 1), 7.40 (4, 2H), 7.21 (d, 2H, ze 8.7 Gy), 6.90 (da, 4H, 15 8 .7 Hz), 4.04 (4, 4H, 1-6.6 Hz), 2.17 (t, 6H); LC/MS: retention time: 26.51 minutes; purity: 9595; MO (mass/charge): 365 (MNE). 7.3.48 M2,M4-bis(4-ethoxyphenyl)-6-chloro-2,4- Similar to the preparation of M2,Ma-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (K926072) pyrimidinediamic, M2 ,M4-bis(4-ethoxyphenyl)-b-chloro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4,6-trichloropyrimidine and 4-ethoxyaniline. IN

NMR (SOSISU C 7.424, 2.39 Gu 718.2, 5- 8.7 Gm), 6.59 (9, 2H, 15 6.3

Hz), 6.84 (0, 2H, 1-8.7 Hz), 6.58 (5, 1NU, 4.02 (t, 4H), 1.43 (t, 6H); LC/MS: duration retention: 83.21 minutes; purity: 8799; MS and (mass/charge): 385 (MNE). 7.3.49 M2,M4-bis(3,4-ethylenedioxyphenyl)-5- Amvalologically to preparation 2, h4-bis( 3-tihydroxyphenyl)-5-fluoro-2,4-methyl-2,4-pyrimidinediamine (K926242) pyrimidinediamine, M2,M4-bis(3,4-ethylenedioxyphenyl)-5-methyl-2,4-pyrimidinediamine is obtained as a result reaction of 7,4-dichloro-5-methylpyrmidine and 3,4- stylenoxyaniline.IN NMR(SOSO): IR 7.75 (b5, 1H), 7.06 (0, 1H, 7-2: 2.4 Hz) . 9 Gy), 4.23 (in, 4H). 4.19 (5, 4H), 2.09 (in, ZN); LC/MS: retention time: 22.01 minutes; purity: 10095; MS (mass/charge ): 393 (MNK). 7.3.50 М2,Ма4-bis(3, 4 ethylenedioxyphenyl)-2,4" Similar to the preparation of М2,М4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinedismine (K926743 ) of pyrimidinediamine, M2,M4-bis(3,4-ethylenedioxyphenia)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloropyrimide inu and 3,4-stylenoxyaniline. 1H NMR (0M50-46): 0 10.95 (c, IN), 10.50 (5, 10), 7.84 (b, 2NH, 7.24 (b, 2H)), 6.79 ( i, 2H), 5.40 (in, 2H), 4.24 (5, 8H); РХ/MS: duration of retention: 21.68 minutes; purity: 1005; MC (mass/charge): 379 (MN). 7.3.51 MO Ma-bis(3-hydroxyphenyl)-5-methyl-2,4- | Analogous to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinedismine (K926248) pyrimidinediamine, M2,M4-bis(3-hydroxyphenyl)-5-methyl-2,4-pivimidinediamine is obtained as a result reactions of 2,4-dichloro-5-methylpyrimidine and 3-hydroxyaniline. LC/MS: retention time: 16.76 minutes; purity: 10095, MS (mass/charge) in: 309 (MN). 7.3.52 M2,Ma-bis(3-hydroxyphenyl)-2,4- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (K926249) pyrimidinediamine, M2,M4-bis (3-Hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloropyrimidine and 3-hydroxyaniline. LC/MS: retention time: 16.21 minutes; purity: 1000; MC (mass/charge): 295 (MN), pnya pntiiiitTzhnzhnvTnvTNnzhchtntTNnchtTNnchtnNtchtTaIonTvdwnNlzhlynnnnnnnn o 7.3.53 M2,M4-bis4- Analogously to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-methoxycarbonyl-2-phenylmethyleneoxy) ,4- | pyrimidinediamine, M2,M4-bis((4-methoxycarbonylmethyleneoxyphenia|-2,4-pyrimidinediamine (5926256) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloropyrimidine and methyl 4-aminophenoxyacetate. 1H NMR (0М50-й6): HI 10.7 (B5, IN), 10.28 (B, 1), 7.84 (y,

IN, 7-6.9 Hz), 7.48 (va, 2H)), 7.35 (a, 2H, 3-87 Hz), 6.95 (4, 2H, 1-9 Go), 6.90 ( 4, 2H, other 8.7 Gy), 6.35 (4, 1H, 12 6.9 Hz), 4.81 (5, 2H), 4.79 (5, 7H)), 3.69 (5, ZNU , 3.68 (5, (se)

ZN); LC/MS: retention time: 21.27 minutes; purity: 9894; MS (mass/charge): 439 (ME). (e) 7.3.54 (3 M2,M4 bis4 methoxycarbonyl(alpha- )-M2,44-bis|4-methoxycarbonylalpha- or pyrimidinediamine (K926257) methyl)methyleneoxyphenylI-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloropyrimidine and ()-methyl 2-(4-aminophenoxy)propionate. PH/MS: Ha retention time: 24.09 minutes; purity: 9035; MC (mass/charge): 467 (MN). 7.3.55 M2,MA-bis(4- Analogously to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-(ee) methoxycarbonylmethyleneoxyphenyl)-5-pyrimidinediamine, M2,M4-bis(4- methoxycarbonylmethyleneoxyphenyl)-5-methyl-2,4-methyl-2,4-pyrimidinediamine (5926258) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-methylpyrimidine and methyl-4-aminophenoxyacetate. IN NMR (PM50-d46): 21 10.21 (5, 1H)), 9.65 (5.18), 7.78 (5, PN, 7.42 (44.2, 72.7 and 8, 7 Go), 7.28 (484, 2H, 1- 8.1 Hz), 6.94 (d, 2H, 15 8.47 Hz), 6.85 (4, 2H, 12: 8.7 Go) . : 21.76 minutes; purity: 10095; MS du (mass/charge): 453 (MN). from 7.3.56 (MO, Ma-bio|4-ethoxycarbonyl(alpha- Analogously to the preparation of M21M4-bis/ 3-hydroxyphenium) -5-fluoro-2,4-s methyl)methyleneoxyphenyl|-5-methyl-7,4-pyrimidinediamine, (3-42 h4-bis(4-ethoxycarbonyl(alpha-pyrimidinediamine (KU26259) methyl)methyleneoxyphenia|-5- methyl-2,4-pyrimidineliamine is obtained as a result of the reaction of 2,4-dichloro-5-methylpyrimidine and (k)-ethyl 2444-aminophenoxy)propionate. " 1H NMR (0M50-46X: С 9.9 , 180), 9.35 (B5, 1H), 7.79 (5, 1H), 7.43 (40, 7H, 1- 3.6 and 8.7 Hz), 7.32 (0, 2H, 2- 7.5 Hz), 6.86 (y, 2H, 1- 9 Hz), 6.78 (d, 2H, 7: 8.7 Hz), 4.95 (4.18, 7: 7, 2 Gy), 4.90 sa, IN, 1-72 Hz), 412429, 4H, re 5.7 Hz), 2.10 (v, ZNU, 1.51 (4, zn, 2-63 Go ), 1.47 a, ZN, 1- 6.3 Hz), 1.16 (2, EN, 7- 5.7 Gy); PH/MS:

Go! retention time: 27.41 minutes; purity: 9695; MC (mass/charge): 509 (MN). 7.3.57 M2,M4-bisI2-(a-hydroxyphenyl)stil|-5- Analogous to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4"ke methyl-2,4-pyrimidinediamine (K926397) pyrimidinediamine . PH/MS: retention time: 19.94 minutes; - purity: 10005; MS (mass/mass): 365 (MN).

7.3.58 M2,M4-bis-(3 4 dimethoxyphenyl)-5-nitro- | Analogous to the preparation of y2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-2,6-pyrimidinediamine (2940089) pyrimidinediamine, I42,M4-bis-(3,4-dimethoxyphenyl)-5-nitro-2 ,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-nitrotyrimidine and 3,4-limethoxyacylin. LC/MS: retention time: 28.30 minutes; purity: 10095;

MS (mass/charge): 428 (MNK); 1H NMR (SOSIS): 010.30 (IN, 5), 9.14 (1H, 5), 7.52

Ch1H, 5), 7.08 (ZN, t), 7.00 (IN, a, 2 8.4 Gy), 6.84 (IN, 4, 22 8.4 Gy), 6.76 (IN, 4.12 8.4 Gy), 3.90 (ZN, 8), 3.87 (ZN, 5), 3.68 (ZN, 5), 3.60 (ZN, c). 7.3.59 M2,M4-bis-(4 stoxyphenyl)-3-nitro-7,4- Analogous to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (KO40090) pyrimidinediamine, M2,M4-bio-(4-ethoxyphenia)-5-nitro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,2-dichloro-5-nitropyrimidine and 4-ethoxyaniline.

PH/MS:; duration of detention: 35.9) minutes; purity: 10095; MS (mass/charge): 396 (MNO; IN NMR (SOS): 10.25 (1H, 5), 9.11 (1H, 5), 7.44 (2H, 4, 2- 8.6 Gy) , 7.37

CH, a, 1-9Gy), 6.88 (2H, 4, 1- 8.6 Hz), 6.80 (2H, d, 1- 8.6 Gy), 406 (2H, 4.4: 7 ,2

Ги), 4.02 (2Н, а, 727.2 Га), 145 (3, - 7.2 Hz), 1.42 (NN, 632 7.2 Hz). 7.3.60 M2,M4-bis-(3,4-ethylenedioxyphenyl)-5- Similar to preparation 142, h4-bis(3-hydroxyphenyl)-5-fluoro-2,4-nitro-2,4-pyrimidinediamine (2940095) pyrimidinediamine, M2,M4-bis-(3,4-ethylenedioxyphenia)-5-nitro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-nitropyrimidine and 3,4-ethylenedioxyaniline. LC/MS: retention time: 30.78 minutes; purity: 100;

MS (mass/charge): 424 (MNK); IN NMR (SOSIZU: 0 10.21 (IN, 5), 9.10 (1H, 5), 7.40 75 (IN, 5), 7.11-6.71 (6H, it), 4.29 (4H , 5), 4.25 (AN, 5). 7.3.61 Mother -bis-(4- Analogous to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-ethoxycarbonylmethyleneoxy)phenyl|-5-pyrimidinediamine , M2,m4-bis-|(4-ethoxycarbonylmethyleneoxy)phenyl|-5-nitro-2,4-nitro-2,4-pyrimidinediamine (Ck 940096) pyrimidinediamine is obtained as a result of reaction of 2,4-dichloro-5-nitropyrimidine and ethyl 4-aminophenoxyacetate LC/MS: retention time: 32.48 minutes purity: 9455 MS (mass/charge) y: 512 (MH) 1 NMR (SOSIS) 2 10.22 (1, 5) , 9,13

CH, 5y 7.50 (1H, 5), 7.45 (2H, y, 32 8.7 Hz), 7.38 (2H, 4, 3- 8.7 Hz), 6.93 (2H, d , 15 8.7 Hz), 6.83 (2H, 4, 12 8.7 Hz), 4.67 (2H, 5), 4.63 (2H, 5), 4.29 (2H, d, 2 - 7.2 Hz, 4.28

CH,a, 7.2 Hz), 1.31 (ZH, 2, 72 7.2 Gy), 1.30 (ZY, t, 1: 7.2 Gy). 7.3.62 142,M4-bis4(2,2-difluoro»1,3- Similar to the preparation of M2,m4-bis(3-hydroxyphenyl)-5-fluoro-2,4-benzodioxol-5-yl)-5-nitro -2,4- pyrimidinediamine, M2,M4-bis-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-nitro-2.4-pyrimidinediamine (K940100) pyrimidinediamine is obtained as a result of the reaction of 2,4- of dichloro-5-nitropyrimidine and 2,2-difluoro-5-amino-1,3-benzodioxole. LC/MS: incubation time: 38.15 minutes; purity: 9690; MS (mass/charge): 467 (M); IN NMR (SOSIS): C 10.76 (EN, 5) 049 (IN, 5), 9.20 (IN, 5), 7.74 (2Н, 5), 7.56 (1Н, 8, 25 11 ,4 Gi), 7.33 OH, t), 7.20 se "KIN, t). NN on 7.3.63 Mo, Ma-bis-(3,5-dichloro-4-hydroxyphenyl)- | Similarly to the preparation of M2,M4-bis(3-hydroxyphenyl)-z-fluoro-2,4-5-fluoro-2,4-pyrimidinediamine (2940215) pyrimidinediamine, M2,Mm4-bis-(3,5-dichloro-4- tihydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-lichloro-5-fluoropyrimidine and 3,5-dichloro-4-hydroxyaniline. LC/MS: retention time: 21.26 minutes; purity: 8899; MS (mass/charge): 450 (MU); IN NMR (OM50-46U: (29.96 (1H, 5), 9.59 (Che) (IN, 5), 9.27 (IN, 5), 9.37 (IN, 5), 8.22 (IN, 4, 1: 3.6 Hz), 7.79 (2Н, 5), 774 ОН, 5). 7.3.64 M2, Ma-bis-(3-chloro-4-hydroxy-5-) Similar to the preparation M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-(e)methylphenyl)-5-fluoro-2,4-pyrimidinediamine, M2,M4-bis-(3-chloro-4-hydroxy- 5-methylphenia)-5-fluoro-2,4-pyrimidinediamine (K940216) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and h: 3-chloro-4-hydroxy-5-methylaniline. LC/MS: retention time: 20.55 minutes; purity: 9995; MS (mass/charge): 410 (MN); IN YAME (М5О-46): 19.23 (1Н, 5), 9.07 (1Н, 5), 8.99 (1H, 5), 8.66 (1H, 5), 8.13 (1H, 4, 3-3.6 Hz), 7.59 (2H, 72 Z, Gy), si 7.50 (IN, a, 12: 2.3 Ha), 7.34 (1H, y, 72: 2.3 Gy), 2.27 (ZN, 5), 2.18 (ZB 5). 325 7.3.65 M2,M4-bis-2,3-dimethyl-4- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4- co hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 1M2 ,44-bis-(2,3-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (K940217) pyrimidinedi amine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 2,3-dimethyl-4-hydroxyaniline. LC/MS: retention time: 19.07 minutes; purity: 9995; MS (mass/charge): 369 (MNK); IN NMR (0M5O-a6): 179.21 (1H, 5U, 8.99 (1H, 5), 8.63(1H, 5), 7.92 (1H, 5), 7.84 (IN, and , 1: 3.6 Hz), 6.94 (1Н, 4, З- 8.5 Hz), « 6.85 (IN, и, 7- 8.5 Hz), 6.70 (IN, 4, Г- 8.5 Hz), 6.58 (1H, d, 7- 8.5 Gy), 12 ЗН, 5), 7.06 (ЗН, 5), 2.02 (ЗН, 5), 1, 94 (ZN, 5). from 7.3.66 М2,М4-bis-(4-anstamidophenia)-5-fluoro- Similar to the preparation of 1М2,М4-bis(3-hydroxyphenyl)-5-fluoro-2,4- with 2,4-pyrimidinediamine (K940222) of pyrimidinediamine, M2.M4-bis-(4-acetamidephenyl)-5-fluoro-2 4-pyrimidinediamine and are obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4- and - acetamidine. LC/MS: retention time: 14.82 minutes; purity: 9595; MS (mass/charge): 395 (MNK); IN NMR (OM50-46): 210.33 (1Н, 5), 10.1441Н, 5), 10.07

СН, 5), 8.39 PN, 4, 2-51 Hn), 7.64 (ВН, t), 2.15 (ЗН, 5), 2.13 (ЗН, 5). 7.3.67 M2,Mma-bis(3-isopropylphenyl)-5-fluoro-2,4- | Similar to the preparation of M2,m4-bis-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine K940297 pyrimidinediamine, M2,M4-bis-(3-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine (ee) obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-isopropylaniline. LC/MS: retention time: 29.58 minutes; purity: 98 25,

Kz MS (mass/mass): 365 (MN); 1H NMR (PM50-46): 110.5 (IN, 8), 10.34 1, 5), 5 Na, - 5, Hz), 7.62 (IN, 8, 1-5 8, Hz), 7.53 (AN 5), 7.43 (EN, 0, 3-2 V Go), 7.37 OH, t), 7.29 (1H, 61-81 Gy), 719 (IN, y, 32 7, 8 Hz), 708 (1, 9, 7 7.8 Gy), - 2.88 (2H, t), 1.25 (6H, d, 1 7.2 Gy), 1.201 (6H, a, 2- 72 Hz). (Se) 42) ko 60 b5

7.3.68 M2,m4-bis(3,4,5-trimethoxyphenia)-5- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (926688 ) of pyrimidinediamine, M2,M4-bis(3,4,5-trimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3,4,5-trimethoxyaviline. LC/MS: retention time: 19.55 minutes; purity: 99 95;

MC (mass/charge): 461 (MN). 9 7.3.69 2, M4-bis(2-methyl-5-phenylphenyl)-3- Similar to the preparation of M2,M4-bis(3-tihydroxyphenyl)-5-fluoro-2,4-bromo-2,4-pyrimidinediamine 925800 pyrimidinediamine, M2,144-bis(2-methyl-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamine is restrained as a result of the reaction of 5-bromo-2,4-dichloropyrimidine and 5-phenyl-ortho-toluidine. LC/MS: retention time: 19.54 minutes; purity: 90 0; MC (mass/charge): 422 (MN). 7.3.70 M2,M4-bio(2-methoxy-5-methyl-4- Analogous to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-76 phenylphenyl)-5-bromo-2, 4-pyrimidinediamine | pyrimidinediamine, M2/M4-bis(2-methoxy-5-methyl-4-phenylphenyl)-5-bromo-2,4- (К925801) pyrimidinediamine is obtained as a result of the reaction of 5-bromo-2,4-dichloropyrimidine and 5-methyl -4-phenyl-ortho-anisidine. LC/MS: retention time: 20.99 minutes; purity: 85 20; MS (mass/charge): 583 (MN-). 7371 М2,М4-bis(indole-b-yl)-5-fluoro-2,4- Analogously to М2,М4-bis(3-hydroxyphenyl)-5-fluoro-2.4-pyrimidicdiamine (К926594) pyrimidinediamine M2.М4- bis(indole-b-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and b-aminoindole. LC/MS: retention time: 22.39 minutes; purity: 8590; MC (mass/charge): 359 (MN). 73.72 M2,M4-bis(2-methoxycarbonyl) Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-benzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamic, M2, M4-bis(2-methoxycarbonylbenzofuran-5-1l))-5-fluoro-2,4-pyrimidinediamine (K926004) pyrimidinediamine is obtained as a result of the reaction of 2,4-lichloro-5-fluoropyrimidine and 2-methoxycarbonyl-5-aminobenzofuran. IN NMR (OM50-46): 0 10.3 (in, IN), 10.05 (B, IN), 8.25 (4, IN, 1- 5.4 Hz), 8.06 (in, 1Н ), 7.94 (5, 1), 7.77-7.49 (t, 58), 7.36 (65, IN), 3.89 (5, ZN), 3.87 (5, ZI) . 7.3.73 Mother -bis|d- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-(methoxycarbonylmethyl)phenyl-5-fluoro-pyrimidinediamine, M2,44-bis(3-hydroxyphenyl)-5-fluoro-2,4-(methoxycarbonylmethyl) phenyl|-5-fluoro-2,4-2,4-pyrimidinediamine (K926605) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and ethyl 4-aminophenylacetate. A cross-esterification reaction of a complex ethyl ether with the formation of a corresponding complex methyl ether was also observed. IN NMR (SOSIS): SI 10.62 (5, IN), 5.065 (5, 18), 7.69 10, IN, 72 4.5 Hn), 7.534, 2H, 1- 8.1 Hz), 7 ,43 (0, 2H, 3- 8.7 Hn), 7.30 a, 2H, - 8.4 Pi), 7.20 (4.2H, 1-: 8.4 Hz), 3.73 5, ZN), 3.72 (5, ZNU, 3.67 (5, 2NIU, 3.63 (5, 2H). i. 7.3.74 M2, Ma-bis(2-ethoxycarbonylinpol-5-yl)- Similar to the preparation of M2, Ma-bis(3-hydroxyphenyl)-5-fluoro-2,4-He) 5-fluoro-2,4-pyrimidinediamine (K926616) pyrimidinediamine, I42,144-bis(2-ethoxycarbonylindol-5-yl )-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 2-ethoxycarbonyl-5-indolamine. IN NMR (PM5O-96): 111.83 (5, 1), 11.63 (5, 1H), 9.21 (5, 1H)), 8.99 (5, 1), 8.08 (5, 1H), 8.01 (n, 2А1), 7.49-7, 22 (tv, 4H)), 6.92 (5, 1H), "se 6.63 (5, 1H), 4.29 (d, 4H, 7-7.2 Si), 1.32 (t, 6H); LC/MS: retention time: 2A, 74 minutes; purity: 9995; MS (mass/charge): 503 (MNY). 73.75 M2,MaA-bis(coumarin-6-yl)-5-fluoro-2,4- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4- o pyrimidinediamine (K926617) pyrimidinediamine, M2,M4-bis(coumarin-6-yl)-5-fluoro-2,4-pyrimidinallyamic acid is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and b-aminocoumarin. h--

IN YAM (0M50-46): 278.17 (4, 2H, 2-3.6 Gy), 7.97-7.74 (t, 5), 7.50 (IN, d, 12 8.7 Gy ), 7.309, 1H, 1- 9 Hz), 6.509, 1H, 12 10.2 Hz), 6.40 (y, 1H, 1- 9.3 Gnu; РХ/MS: Ha retention time: 19.05 minutes; purity: 945; MS (mass/mass): 417 (Mn.

Zo 73.76 M2,M4-bis(4-methoxymethyl)coumarin-7- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-(he)yl)-5-fluoro-2 4- pyrimidinediamine pyrimidinediamine, M2,.M4 -bis(coumarin-7-yl)-5-fluoro-2,4-pyrimidinediamine (К926620) is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 7-amino-4-methoxymethylleucoumarin . IN NMR (PM50-46): (1 10.38 (5, 18), 8.42 (4, 1H, 2-3 Gy), 8.28 (t, IN), 8.05-7.93 (t, 2), 7.77-7.50 (t, 4H), 6.31 (5, IN), 6.29 (5, 1 NU, 4.66 (5, 2), 4.65 (5, 2H ), 3.43 (5. ZNU, 3.41 (5, ZNI; LC/MS: MS (mass/weight): 505 (MIN). " 7.3.77 M2,M4-bis(3-(hydroxymethyl)phenyl )-5- Analogously to the preparation of 2, h4-bis(3-hydroxypheny)-5-fluoro-2,4- fluoro-2,4-pyrimidinediamine (K925757) tnrymidinediamine, M21h4-bis(3-(hydroxymethyl)phenyl)-5 -fluoro-2,4-pyrimylidenediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrymyline and 3-aminobenzyl alcohol, NMR (COUPLED): 7.904, 1.3-3.3 Hn), 7.71 (iv) , and 18), 7.614, IN, 1-6.9 Hz), 7.504, 1H, 2: 6.0), 7.47 (in, 1), 731 (6 1H,2- V Gu, and 2 ,22 1H, 1-28, Ha), 7104, 1H, )- 6.9), 6.97 (y, 18, 12: 7.5 Hz), 4.63 (5, 4H);

LC/MS: retention time: 15.36 minutes; purity: 10092; MS (mass/mass): 347 (MN). 7.378 MUMa-bis(2K)-hydroxy415)-methyl-2-Amnapogic preparation of M2,M4-bis(3-hydroxyphenyl-5-fluoro-2,4-phenylethyl-5-fluoro-2,4-pyrimidinediamine | pyrimidinediamine, M2 ,M4-bishoK)-hydroxy-(15)-methyl-2-phenylethyl|-5-fluoro-2,4- (22) (8925767) pyrimidinediamine is obtained as a result of the reaction of 7,4-dichloro-5-fluoropyrimidine and (18 ,25)-(-)-norephedrine. 1H NMR (acetone-d6): 010 0)51177.49-7.42 (t, 4H), 7.38"

Kkz 1.19 (t, NI), 6.09 (6, 1H, 1-90 Gy), 5.73 (4, 1, 7- 7.5 y), 5.616, 1H, 3-93 Gy), 5.044, IN, 2- 3.6 Gy), 4.974, 1H, 752.7 Gy), 4.74 (5, 1), 4.48 (p5, IN), 4.30-4.25 - (t , TN)U, 1.09 (8, 18, 2-6, Gi), 1.03 (4, 1H, 1- 6.6 Hz); LC/MS: 20 hold duration: 21.56 minutes; purity: 9895; MS (mass/mass): ZMK), (se) 73.79 Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4- 42)

F) ko 60 b5 fluoro-2,4-nyrimidinediamine (K925768) pyrimidinediamine, M2,M4-bis(2-thyloxy-2-phenylethyl)-5-fluoro-2 4-pyrimidinediamine. obtained as a result of the reaction of 2,4-dichloro-5-pheorpyrimidine and 2-amino-1-phenylethanol. IN NMR (acetone-4db); SI 8.15 (5, 1H), 7.46-7.22 (t, 100), 5.01 (ad, 1H), 4.91 (44, 18), 4.78 (44, 19), 3.86-3.18 (t, 5H); LC/MS: retention time: 19.64 minutes; purity; 89 92; MC (mass/charge): 369 (MN). 7.3.80 M2,M4-bis(furfuryl)-5-fluoro-2,4- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (KU25759) pyrimidinediamine, M2,M4 -bis(furfuryl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and furfurylamine. IN NMR (SOSIZ)U: 07.72 (65, 1H), 7.38 (ad, 2H, He 1.8 and 7.5 Hz), 6.34-6.30 (pi, 2H), 6, 22 (40, 2H, 31: 2.4 and 9.9 Gy), 5.153 (in, 2H), 4.63 (y, 2H, 7- 6.0), 4.54 (0, 2H, ze 6 ,0); 19E

NMR (SOSIZ): -48621; LC/MS: retention time: 97.27 minutes; purity: 9795;

MS (mass/charge): 289 (Mn. 70 7.3.81 M2,M4-bisipiperonyl)-5-fluoro-2,4- Similar to preparation 42, M4-bis(3-tihydroxyphenyl)-5-fluoro-2,4 - pyrimidinamine (5925770) of pyrimidinediamine, M2,Ma4-bis(piperonyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and piperonylamine. 1H NMR (Srazukh popi 6.78-6.69 (t, BN), 5.93 (5, 2), 5.91 (5.2H), 5.514, 2H, 25 5.7

Ha), 4.43 (d, 2H, 25 5.1 Gy); 192 NMR (SOSISU: -45257; LC/MS: retention time: 22.06 minutes; purity: 965, MS (mass/charge): 397 (MIN. 7.3.82 MO Ma-dibenzyl-z-fluoro-2,4 - Similarly to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (K925772) pyrimidinediamine, MO, Ma-bis(benzyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction 2,4-dichloro-5-fluoropyrimidine and benzylamine. 1H YAME (SOCI3): 127.69 (B5, 18), 7.35-7.24 (t, 10H), 5.63 (05, 1H), 5 .27 (B5, 1H), 4.61 (0, 2H, 1-60 Hz), 4.55 (y, 2H, 1- 6.0 Hn); 192 NMR (SOSIZ): -48580; LC/MS: duration retention: 23.73 minutes; purity: 10005; MS (mass/charge): 309 (MN). 7.3.83 M2,M4-bis(3,4-methylenedioxyphenyl)-5- Analogously to the preparation of M2,M4-bis(3 -hydroxyphenia)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (5925775) pyrimidinediamine, M2.M4-bis(3 4-"methylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3,4-methylenedioxyaniline. 1H NMR (SOSIS): (17.86 (B, IN), 7.27 (t, IN), 7.19 (t, 18) , 6.89 (ai, 2, 1- 21 and 8.1 Hz), 6.89 (44, 2H, 15-16 and VA Hn), 6.73 (0 2H, 3 V Gu, 5.97 (z, 2H)), 5.92 (5, 2H); 19E NMR (SOSISU: -47591; LC/MS: retention time: 21.74 h; purity: 9790; MS (mass/charge): 369 (MNK). 7.3.84 M2,M4-bisu2-(4-hydroxyphenyl) style|-5- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (925791) pyrimidinediamine, M M4-bis(2h(4-hydroxyphenyl)ethyl |-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and tyramine. IR c and NMR (ЮМ50-46): 9.17 (65, 1Н), 8.22 ( 65, 18), 6.99 (4, 4H, 2-8.1 Hz), 6.65 (4, YAN, o

Te 8.1 Gy), 3.48-3.43 (t, 4H), 2.72 0, 4H, 1: 7.7 Hz); LC/MS: retention time: 19.19 minutes; purity: 100 95; MC (mass/charge): 369 (MN). 7.3.85 M2,Mm4-bis(4-cyanophenyl)-5-fluoro-7,4- Similar to the preparation of M2,M-4-bis(3-hydroxyphenyl)-5-fluoro-4-pyrimidinamine, pyrimidinediamine (K945057) M , ma-bis(4-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 4-aminobenzonitrile and 2,4-dichloro-5-fluoropyrimidine. 26 (d, 1- 8.7 Hz, 2 NU, 7.36 (8, 1- 9.0 Hz, 2 H), 7.43 (4.1- 8.7 Hz, 2 NU, 7.50 (6, 2-8.7 Gm, 2 NU, 7.86 (j, 15 3.6 Hz, 1 N), 9.9 (g, 1 N, MN), 9.51 (be, 1 N, MN); 19E o

NMR (282 MGy, OM5O-y6y: 0 -161.48; 1: 27.15 typ.; 10095, MS (mass/charge): 331.00 (MN). 7.3.86 M2,M4 bis(4-ethylphenyl )-5-Ffluoro-2,4- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4- - pyrimidinediamine (K926234) pyrimidinediamine, M2.M4-bis(4-ethylphenyl)-5 -fluoro-2,4-pyrimidinedisms are obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-ethylaniline, 1H NMR s (SOSIS): 18.83 (b5, IN), 7.77 (4, 1H. 7» 3.9 Gy), 7.48 (d, 2H, 3-87 Hn), 7.40 (y, 2H, 3-2 8.7 Sy), 7.31 (be, IN), 7, 18 (4, 2H, I 8.7 Hz, 7.11 (9, 2H, 2: 8.7 Hn), 2.68-2.61 (t, s 4H), 1.28-1.21 ( t, NU; RH/MS: retention time: 29.17 minutes; purity: 00 90; MS (mass/charge): Z3Z'YAMN k). 7.3.87 m2,/ma-bis(3-chloro-4- hydroxyphenia).5- Analogous to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4" fluoro-2,4-pyrimidinediamine (K926675) pyrimidinediamine, M2,M4-bis(3-chloro-4- hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-hydroxyaniline. IN NMR (SOZOR): 127.83 (9, 1H, re 4.2 Gy), 7.59 (0, IN, 2- 2.4

Gy), 7.53 (4, 1H, 4- 2.4 Gy), 7.40 (44, 1H, 1- 2.4 and 8.7 Hz), 7.20 (60, 1H, Ge 2, 4 and 8.7 -in

Gy), 6.89 (y, 1H, 1-8.7 Gy), 6.81 (y, 1H, 1-8.7 Hz); 19E NMR (SUZOI): -478652; with LC/MS: retention time: 17.89 minutes; purity: 99 90; MS (mass/charge): 382 (Mn. ; t 7.3.88 2,Mm4-bis(3-chloro-4- Analogous to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4- ( gtoxycarbonylmethyleneoxy of phenyl-5-pyrimidinediamine, M2,M4-bis|3-chloro-4-(ethoxycarbonylmethyleneoxy)phenyl|-5-fluoro-fluoro-2,4-pyrimidinediamine (K926676) 2,4-pyrimidinediamine is obtained as a result of reaction 2, 4-dichloro-5-fluoropyrimidine and 3-chloro-4-(ethoxycarbonylmethyleneoxy)aniline. IN NMR (SOSISU: (17.93 (b5, 1H), 7.67-7.65 (t, 2H), 7.41 (44, 1H, 1- 3.0 and 9.3 Gy), 7.26 (44, 1H, 1- 2.7 and 9.3 Hz),

Go! 6.92-6.85 (t, ZN)), 6.69 (4, 1H, 3: 2.4 Gy, 4.71 (5, 2H), 4.66 (5, 2H), 4.32 -4.23 (t, 4H), 1.33-1.27 (t, 6H); 19E NMR (SIZH3): -47274; LC/MS: retention time: t 27.51 minutes; purity: 97 90; MS (mass/charge): 553 (MN). 7.3.89 2, iMA-bis(3-fluoro-4-hydroxyphenyl)-5- Similar to the preparation of M2, M44-bis(3-hydroxyphenia)-5-fluoro-2 ,4- - fluoro-2,4-pyrimidinediamine (K926681) pyrimidinediamine, M2,M4-bis(3-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro- 5-fluoropyrimidine and 3-fluoro-4-(Ce) 42) co 60 b5 tihydroxyaniline. IN NMR (SOSIZ): 017.83 (4, NU, 7.53 (49, TA), 7.424, 1), 752 (da, 187), 7.03 (49, IN", 6.89 (4, 18), 6.83 (5, NN), 6.80 (5, 1Н)), 6.78 (8, 13; 19E NMR (SOSIZU: -390060, -39165, -47835; LC/LMS: retention time : 15.27 minutes; purity: 95 95; MS (mass/charge): 349 (MH). 73-90 M2,Ma-bis(3-acetamylphenyl)-5-fluoro- Analogously to the preparation of M2,M4-bis(3 -hydroxyphenyl)-5-fluoro-2,4- 7,4-pyrimidinediamine (K926682) pyrimidinediamine, M2,Ma-bis(3-acetamidophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 7,4- of dichloro-5-fluoropyrimidine and 3-aminoacetanilide. IN NMR (0M50-46): 10.24 (B5, IN), 10.03 (5, 1H), 9.94 (5, IN) 8.20 (4, 1H, 3: 4.8 Hz), 7.91 (Be, IN), 7.68 (65, IN), 7.43 (y, 1H, 1- 8.1 Hn), 7.35-7, 30 (t, 28), 7.24-7.19 (t, 20), 7.11 (6, 1, 2- 8.1 Hz), 2.03 (in, ZNU, 2.01 (in, ZN); LC/MS: retention time: 15.10 minutes; purity: 99 U5; MS (mass/charge): 395 (MI). 7.3.91 M2,M4-bis(2-fluoro-4-thiproxyphenyl)- 5- Similar to the preparation of M2,M4-bis(3-hydroxyphenine)-5-fluoro-2,4-fluoro-2,4-pyr myidinediamine (К926683) pyrimidinediamine, 2, Mch4-bis(2-fluoro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 2-fluoro-4- hydroxyaniline. IN NMR (7М50-46): ГИ9.78 (5, 1Н), 9.50 (5, 1Н), 8.75 (5, 1), 8.06 (5, 1Н), 7.87 (4, TA, 1242 i), 7.25-7.18 (t, 28), 6.61 (46, 1H, 1- 2.4 and 12.3 Go), 6.55-6.47 (ti, NO ), 6.39 (49, 1H, 7: 1.8 and 8.7 Gy); LC/MS: retention time: 15.52 minutes; purity: 99 95; MS (mass/charge): 349 (Mn. 7.3.92 M2,M4-bis(4-isopropoxyphenyl)in 5-fluoro- Analogous to the preparation of IR2,Im4-bis(3-hydroxyphenyl)-5-fluoro-2,4- 2,4-pyrimidinediamine (5926701) pyrimidinediamine, M2,M4-bis(4-isopropoxy)phenyl)-5-fluoro-2,4-pyrimidineliamine is obtained as a result of the reaction of 7,4-dichloro-5-fluoropyrimidine and 4-isopropoxyaniline. 1H NMR (SUOSHIZ)U: 17.89 (65, 1H), 7.47 (d, 2H, 1-8.7 Hz), 7.38 (4, 2H, 3-9 Gy), 6.87 ( 3, 2, 1- 9.0 Hz), 6.83 (y, 2H, 1- 8.7 Gy); LC/MS: retention time: 27.51 minutes; purity: 98 92; MS (mass/charge): 397 (MIN). 7.3.93 М2,Ма-bis(3,4-ethylenedioxyphenyl)-5- Analogous to the preparation of М2,М4-bis(3-hydroxyphenyl)-5-fluoro-2,4-bromo-2,4-pyrimidinediamine (K925771) pyrimidinediamine , M2,MA-bis(3,4-ethylenedioxyphenyl)-5-bromo-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-bromo-2,4-dichloropyrimidine and 3,4-ethylenedioxyniline. 1H NMR (SOSIZU: 018.07 (65, IN), 7.16 "9, IN, 1" 3.0 Gy), 7.10 (Y1H,1e2.7 Gy), 6.98-6.93 (t, 2H), 6.90-6.75 (t, ZNU, 4.28-4.21 (t, 8H); PH/MS: retention time: 22.61 minutes; purity: 10095; MS (mass/charge) : 458 (МН). 7.3.94 М2МА-bis(3-hydroxyphenyl)-5-bromo-2,4- KO25778) of pyrimidinediamine, м2,1х4-bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine is obtained as a result of the reduction of 5-bromo-2,4-dichloropyrimidine and 3-aminophenol.

NMR (2M5O-y6u: C: 9.99B6, 1H), 9.34 (vv, 1NU, 8.30 (5, 180), 7.15 (0, 1H, 15 8.4

Hz), 7.06-6.97 (t, 2), 6.94-5.92 (t, 2H), 6.80 (B5, 1H), 6.62 (5.1H, 3-81 Hz), 6.43 o (0, IN, 1-7.8 Gy); LC/MS: retention time: 18.48 minutes; purity: 97925; MS (mass/charge): 374 (MN.Yu). 7.3.95 m2/ma4-bis(4- Analogous to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-ethoxycarbonylmethyleneoxy)phenyl|-5-pyrimidinediamine, M2,M4-bis/ 4-( Stoxycarbonylmethyleneoxy)phenyl)-5-bromo-2,4-bromo-2,4-pyrimidinediamine (K925779) pyrimidinediamine is obtained as a result of the reaction of 5-bromo-2,4-dichloropyrimidine and (Ce)zo ethyl 4-aminophenoxyacetate. IN NMR (TM8O-4b): 19.12 (in, 1), 8.48 (5, 19), 8.11 (5.1), 7.42 (9, YAN, 72 8.7 Hz), 6.890, 2H, 3-5 9.0 Gy), 6.71 (y, 2H, 35 9.3 Hz), 4.78 F (85, 2H)), 4.06 (5. 21H), 4, 20-4.10 (t, 4H), 1.23-1.16 (t, 6H); LC/MS: retention time: 25.82 minutes; purity: 9495; MC (mass/charge): 546 (MN). "- 7.3.96 M2,Ma-bis(4-hydroxyphenyl)ethyl|-5- Analogous to the preparation of M2,Ma4-bis(3-hydrokeifenia)-5-fluoro-2,4-bromo-2,4-pyrimidinediamic ( 5925792) pyrimidinediamine, M2,M4-bis|2-(4-ylproxyphenyl)ethyl|-5-bromo-2,4-pyrimidinediamine Ga is obtained as a result of the reaction of 5-bromo-2,4-dichloropyrimidine and tyramine. 1

NMR (0M50-46): 0 7.83 (5, 1H), 6.96 (4, 4H, 1-81 Go), 6.63 (y, 4H, 1-81 Hz), 3.54-3 .42 (t, 2NI), 2.74-2.66 (t, 2H), 2.74-2.66 (t, 4H); duration of detention: (c to) 29.10 minutes; purity: 100 95; MC (mass/charge): 430 (MN). 73.97 M2m4-bis(2-phenylphenyl)i-5-bromo-2,4- Similar to the preparation of IM2,44-bis(3-tihydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (925798) pyrimidinediamine, M2Ch4-b1s( 2-phenylphenyl)-5-bromo-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-bromo-2,4-dichloropyrimidine and 2-aminobiphenyl. 1H NMR (SOSISU: 17 8.34 (d, 1H, 75 8.1 Hz), 8.27 (0, 1H, 22 8.1 P), 8.00 (5, 18), « 7.51- 7.18 (t, 17), 6.95 (in, IN); LC/MS: retention time: 18.87 minutes; purity: 97 95; MS (mass/charge): 495 (MN). shsh s 7.3 .94 M2,M4-bis(2-methoxy-5-phenylphenyl)-5- Similar to the preparation of M2Ch4-bis(3-hydroxyphenyl)-5-fluoro-2,4-bromo-2,4-pyrimidinediamine (K925799) pyrimidinediamine, 2,144-bis(2-methoxy-5-phenylphenyl)-5-bromo-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-bromo-2,4-dichloropyrimidine and 5-phenyl-ortho-anisidine. IN NMR ( ОМ 5О0-й6): О 8.26 (t, 2Н), 8.05 (t, 2Н), 7.39-7.21 (t, 128), 7.17 (44.1Н, 1-24 and 8 ,1 Go 711 (a, 1H, 2-87 Gy), 7.054, 1H, 129.0 Hz), 3.88 (5,

ЗН), 3.83 (5, ZNU; РХ/MS: duration of retention: 20.51 minutes; purity: 985 55; MS (mass/discharge): 554 (MNE). so 7.3.99 M2/Ma-bis( 4-methoxy-3-phenylphenyl)-5- Similar to the preparation of TM2,MA-bis(3-hydroxyphenyl)-5-fluoro-2,4-bromo-2,4-pyrimidinediamine (5925802) pyrimidinediamine, M2,M4-bis( 4-methoxy-3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-bromo-2,4-dichloropyrimidine and 3-phenyl-para-anisidine hydrochloride with the addition of tristylamine. IN YAM? (0М50- 46); 7 8.26 (t, 2H), 8.06 (t, 2H), 7.38-7.25 (p, 128), 7.18 (y, 1H, 12: 2.4 and 8 ,1 Go), 7.12 (EN, shk 8.7 Gy), 7.054, 1H, 8.7 Go), 3.89 (5, ZN), 3.83 (5, ZN); LC/MS: duration of 20 retention: 36.77 minutes; purity: 98 96; MS (mass/charge); 554 (MN). 42) ko 60 b5

73100 M2,M4-bis(3-phenylphenyl)-5-bromo-2,4- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (925803) pyrimidinediamine, M2,M4 -bis3-phenylphenyl)-5-bromo-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-bromo-2,4-dichloropyrimidine and 3-aminobiphenyl.

IN NMR (OM 5O-d6): 1 9.86 (b, 18), 9.20 (65 1), 8.33 (5, 181), 7.79 (b5, IN, 7.18 (Be, 18), 7.61 (4, 155, 7.56-7.51 (t, 2H), 7.48-7.23 (t, 11), 7.17-7.04 (t, 28);

ВХ/МС: duration of retention: 19.52 minutes; purity: 80 95; MC (mass/charge): 494 (MN). 7.3.0 M2,MA-bis(3,4-ethylenedioxyphenyl)-5- Avalogous to the preparation of M2,Im4-bis(3-hydroxyphenyl)-5-fluoro-2,4-cyano-2,4-pyrimidinediamine (925773) pyrimidinediamine , 42, M4-bis(3,4-ethylenedioxyphenyl)-3-cinano-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-cyanopyrimidine and 3,4-ethylenedioxyaniline. IN NMR (0M50-46y: I) 9.69 (b5, 1), 9.28 (5, 18), 8.40 (5, 10), 7.165-6.89 (t, 4H), 6.79 (d, 1H, 7: 9.0 Hz), 6.65 (v, 1), 4.22 (5, 4H), 4.16 (5, 70 4nH)y; LC/MS: retention time: 24.42 minutes; purity: 93rd; MS (mass/charge): 404 (MNY, 7.3102 MM -bis(3z-hydroxyphenyl)-5-cyano-2,4- | Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4 - pyrimidinediamine (29725774) pyrimidinediamine, M2,M4-bis(3-hydroxyphenyl-5-cyano-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-cyacopyrimidine and 3-hydroxyaniline. TN NMR (0ОМ5О0-4й6 ): GP 9.73 (B5, 1), 9.40 (5, 1H), 9.33 (be, IN), 9.24 (5, 1H), 8.47 (5, 1), 7.204, 18, 37.5 Gy), 711 (61.3-7.5 Hz), 7.09-7.02 (t, 2H), 6.99-6.89 (t, ЗН), 6.54 ( 4, 1H, 3-7.2 Gy), 6.37 (44, 1H, 1-1.8 and 8.4 Gy);

LC/MS: retention time: 19.71 minutes; purity: 9795, MS (mass/mass); 320 (Mich). 7.3.403 M2,M4-bis(A- Analogously to the preparation of IM2,M4A-bis(3-hydroxyphenyl)-5-fluoro-2,4- (ethoxycarbonylmethyleneoxy)phenyl|-5-pyrimidinediamine, M2,Ich4-bis(4- (ethoxycarbonylmethyleneoxy)phenyl|-5-cyano-2,4-cyano-2,4-pyrimidinediamine (5925775) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-cyanopyrimidine and ethyl 4-aminophenoxyacetate. IN NMR (SIZO: si 7.80 (with, 1H), 7.40 (8, 4H, 1- 8.7

Gi), 6.994Н, 1 9.0 Hz), 6.82-6.75 (t, 2Н). 4.60 (B5, 4H), 4.29-4.25 (t, 4H), 1.32-1.26 (t, 5H), LC/MS: retention time: 28.50 minutes; purity: 100 95; MS (mass/charge): 493 (MN.Yu). 1.3104 VK935192: M2, M4-bis(I-methyl-indazoline- Pyrimidinediamine: pyrimidinediamine, M2, M4-bis(1-methyl-indazolin-5-yl)-5-fluoro-2,4-pyrmidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoropyrimidine and 1-methyl-3-aminoindazole. IN NMR (0M50-46): 1710.65 (5, 1H), 10.41 (5, 1H), 8.29 (y, 1H, 7-sem 5.3 7), 7.98 (5, 1 ), 7.79 (y, 2H, 12: 94 Hyd), 7.69-7.54 (t, 4H)), 7.35 (04, 1H, 72 1.7 and 9.4 Hz), 4 .03 (5, ЗН), 4.01 (5, 3Н).. РХ/MS: retention time: 16.86 minutes; Gee)

ШЩЩХХИ0И2025250 rovy yusuyuyutmnia 7.3.105 K935205: M2,Ma-visi1- Analogously to the preparation of 5-fluoro-IM2,M4-bis(3-tihydroxyphenyl)-2,4- (methoxycarbonylmethyl-indazolin-6b-yl|-. | pyrimidinediamine, M2,M4-bis| 1-(methoxycarbopyl)methyl-indazolin-b-yl)-5-fluoro-5-fluoro-2,4-pyrimidinediamine 2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5- of fluoropyrimidine (Te) and b-amino-1-(methoxycarbonyl)methyl-indazoline. IN NMR (OM5O-46): 119.59 (in, 1H), 9.45 (5, 1H), 8.18 (4, 1H, 3-3.5 Hz), 8.11 (in, 1) , 8.04 (in, 1H)), 7.95 18, 1H)), 7.93 (5, 18, 7.69 (8, 1H, /- 8.8 Gy), 7.58 (4, 1H, 7- 8.8 Gy), 7.48 (84, 1H, 1- 1.7 and 8.8 Hz), (o) 7.32sa, 1H, 1-5 8.8 Hz), 5, 17 (5, 2NI), 4.88 (5, 1, 3.58 (5, ZN), 3.58 (5, ZN). PH/MS: retention time: 17.80 minutes; purity: 9995; MS (mass/charge): 505 (MNY). chi! 7.3106 k935211: M2,M4-visY - Similar to the preparation of IM44(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(methoxycarbonyl)methyl-indazoline-5 -yl|)-|hydroxyphenyl)-2,4-pyrimidinediamine, M2,M4-bisi 1-(methoxycarbonyl)methyl-c 5-fluoro-2,4-pyrimidinediamine indazolin-b-yl|-5-fluoro-2, 4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and b-amico-1-(methoxycarbonyl)methyl-indazoline. IN p

NMR (ОЮМ50-46): 19.37 (5, 1), 9.17 (5, IN), 8.11-8.06 (t, ЗИ), 7.94 (в, 1Н), 7.70 (5, 1), 7.63 (5, 2H), 7.46 (5, 2H), 5.40 (5, 2H), 5.31 (5, 2H), 3.67 (5, Н) , 3.64 (5, ZN).

LC/MS: retention time: 17.06 minutes; purity: 9695; MC (mass/charge): 505 (MN). 7.3.107 K935188: M7,M4-bis(indazolin-b-yl)-5- Similar to the preparation of 5-fluoro-M2,M4-bis(3-hydroxyphenyl)-2,4-" fluoro-2,4-pyrimidinediamine pyrimidinediamine . IN NMR (2M 50-96): 79.80 (5, 1H), 9.65 (5, 18), 8.204, IN, 1-s AG), 81 (5, 1H), 7.96 (5, IN), 7.93 (8, 1H), 7.89 (5, 1H), 7.69 (9, IN, 1» 8.8 Gy), 7.514, IN, 1-83 Hz), 7.54 (49, 1, 1-2 1.7 and 8.8 Gy), 7.29 (40, 1, 72 1.7 and 8.8 Hzu; x z» РХ/MS: retention time: 15.17 minutes ; purity: 9496; MS (mass/charge): 361 and (MN. 7.3108 8935189: M2,M4-bis(innazoline -5-1l)-5- Analogously to the preparation of M2,M4-bis(3-hydroxyphenyl)-5- fluoro-2,4-fluoro-2,4-pyrimidinedismine of pyrimidinediamine, M2,M4-bis(indazoline-5-1l)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 5-aminoindazole. .05 (5, 19), 7.92 45. 1H)), 7.82 (5, 1H)), 7.68 (5, 1), 7.52-7.52 (t, 2H), 7 .44 (0, 1, 1-88 Gy), ke 7.34 (44, 1, 1-17 and 8.8 Gy); LC/MS: retention time: 14.33 minutes; purity; 10095; MC (mass/charge): 361 (MN). shk 7.3.109 M2,m4-bis(1-ethoxycarbonyl-2- Analogous to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-methylpronyl)-5-cyano-2,4-pyrimidinediamine, M2/M4-bis(1-ethoxycarbonyl-2-methylpropyl)-5-cyano-2,4-

He tyrimidinediamine (K925814) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-tskanpyrimidine and 42) ko 60 b5 complex valine ethyl ether. TN NMR (SOSIZU: 0 8.15 (5, 17), 5.20 (y, 1, 15 8.4 Hz), 5.67 (а, 1Н, 25 8.1 Hz), 4.66-4 .62 (p), IN), 4.50-4.46 (t, 1), 4.25-4.13 (t, 4H), 2.27-2.14 (t, 2H), 1.31- 1.24 (t, EN), 1.00-0.94 (t, I2NU; RH/MIS: retention time: 30.41 minutes; purity: 98 y; MS (mass/charge): 392 (MH). 73.10 М2,М4-bis(I-methoxycarbonyl-3- Analogously to the preparation of М2,Ма4-bis(3-hydroxyphenyl)-5-fluoro-2,4-s methylbutyl)-5-cnan-2,4-pyrimidinediamine, М2. 144-bis(1-methoxycarbonyl-3-methylbutyl)-5-cyano-2,4-pyrimidinediamine (2925815) torimidinediamine is obtained as a result of the reaction of 7,4-dichloro-5-cyanopyrimidine and leucine methyl ether. of rotamers C 8.15 (5, 1H), 6.10 and 5.49 (24, 1.42 8.1 Hz), 5.53 (a, 1H, 12 5.4 G and), 4.80- 4.67 (t, 1), 4.57-4.48 (t,

IN), 3.73 (z, ZN), 3.71 (in, ZN), 1.78-1.60 (t, 6H), 0.97-0.89 (t, 12H); LC/MS: retention time: 30.33 minutes; purity: 91 95; MS (mass/charge): 392 (MNK). 73.1 М2,Ма-bis(methoxycarbonylbenzyl)-5- Similar to the preparation of м2,М4-bis(3-hydroxyphenyl)-5-fluoro-2,4- cnan-2,4-pyrimidinediamine (8925819) pyrimidinediamine, М2.М4-bis (Methoxycarbonylbenzyl)-5-pyrene-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-cnanpyrimilic and pheniaglycine methyl ether. IN. NMR (SOSIZ)U; a mixture of rotamers (1 8.15 (5, 1H), 7.59-7.60 (t, 1, 7.42-7.32 (it, 1OH), 6.20 and 5.73 (29, 1H, 1- 6.6 Gy), 6.14 and 5.65 (4, 1H, 1-63 Go), 5.55 (4, IN, 126.3 Hyd), 5.39 0, IN, 2 7, 2. Hz), 3.79 and 3.78 (25,

ZNI), 3.67 and 3.65 (25, ZN); LC/MS: retention time: 30.22 minutes; purity: 91 95; MS (mass/charge): 432 (Mn. 7.3L12 M2,Mma-bisi4- Analogously to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-"ethoxycarbonylmethyl)phenyl|-5-cyano- pyrimidinediazmine, Ch2.M4-bis4-(ethoxycarbonylmethyl)phenip-5-cyano-2,4-2,4-pyrimidinediamine (5926662) pyrimidinediamine is restrained as a result of the reaction of 2,4-dichloro-5-cyanopyrimidine and ethyl 4-aminophenylacetate. IN NMR (SOSIZ): P 8.29 (5, IN), 7.46 (29, 4Н, 1-78

Hz), 7.28 (4, 2, 1- 8.1 Go), 7.194, 2H, 1- 8.1 Hz), 4.16 (24, 4H, 7- 6.3 Hz), 3.64 (5, 2), 3.59 (5, 2H), 1.30-1.23 (t, SNI); LC/MS: retention time: 29.29 minutes; purity: 9355; MC (mass/charge): 461 (MN). 7.3.113 K935000: M2,Ma-bis(2-methoxy-5- Similar to the preparation of 5-fluoro-M2,M4-bis(3-hydroxyphenyl)-2,4-phenylphenyl)-5-methyl-2,4-pyrimidinediamine . NN NMR (SOSIiZ i SOZOU 7.764, 1H, 1223 Hz and 7.57 (5, IN). 7.56 (in, IN), 7.02-6.85 (t, 8NI), 6.86-6.80 (t , 4H), 6.72 (y, 2H), 3.73 (5,

ZN), 3.72 (5, ZN), 2.07 (5, ZN); LC/MS: retention time: 3.53 minutes, purity: 9792; MS (mass/charge): 489 (MAN). 7114 ko935001: M2,M4-bis|!(2-methyl-5- Analogously to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-7,4- phenylphenylphenyl-5-methyl-2,4-pyrimidinediamine . 1 NMR(SOSIS): I 7.59-7.55 (t, 1H), 7.45(6.2H, 312 3.6 Gy), 7.26-7.17 (t, 6H)), 7.09 -6.98 (t, NI), 2.36 (in ZNU, 2.22 (z, ZN), 2.21(5, ZN);

LC/MS: retention time: 32.44 minutes; purity: 9095; MS (mass/charge): 457 (pl. (se) 7.4.115 k935002: M2.M4-bis|(4-methoxy-3- Analogous to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2 ,4-phenyl)phenyl|-5-methyl-2,4-pyrimidinediamine, M2,M4-bis|(4-methoxy-3-phenyl)phenyl|-5-methyl-2,4-(o)pyrimidinediamine pyrimidinediamine are obtained as a result of the reaction of 3-phenyl-4-aniziline hydrochloride and 2,4-dichloro-5-methylpyrimidine with the addition of diisopropylethylamine.IN NMR h: (SOSIS): P 8.15 (y, IN, 122.3 g), 7.76, 1H, 3-2 2.3 Hz), 7.71 (5, 1 H), 7.598, EN), 7.16 -7.03 (t, VN), 6.98-6.81 (5), 3.96 (z, ZN), 3.89 (5, ZN), 2.21 (in, ZN); LC/MS: retention time: 32.01 minutes; purity: 9995; MS (mass/charge) in: 489 (MNK). se 7.34116 KO35003: M2,M4-bis(4-phenyl-2-methoxy- | Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-

Zo 5-methyl)phenyl|-5-methyl-2,4-pyrimidinediamivu, M2,M4-bis(4-phenyl-2-methoxy-5-methyl)phenyl|-5-methyl-2,4- (ge) pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 5-methyl-4-phenyl-2-anisidine and 2.4-dichloro-5-methylpyrimidine. 1 NMR (SOCI3U: 9.25 (bg5.1H), 8.17 (5.18), 7.77 (.1H, 1-64 Hz), 7.66 (8, 215), 7.43-7.25 (t, 10), 6.79 (5, 2H), 3.91 (5, ZN), 3.85 "z, ZNU, 2.20 (5, ZN), 7.09 (z, ZN), 2.02 (5, ZN); RH/MS: retention time: 31.10 minutes; purity: 10090; MS (mass/charge); 517 (MN. « 7.3.117 koz5004: M2.Ma4-bisi (di- (4- Analogous to the preparation of M2,M4-bis(3-tihydroxyphenyl)-5-fluoro-2,4-methoxyphenyl)|methyl|-5-fluoro-2,4- pyrimylidenediamine, M2.M4-bis (li-(4 -methoxyphenyl|methyl|-5-fluoro-2,4- shsh pyrimidinediamine pyrimidinedigmine is obtained as a result of the reaction of 1,1-di(4-anisyl)methylamine and 2,4-dichloro-5-fluoropyrimiline. : 7 7.91 (4, 1H, 12 2.3

GT), 7.18 (4, VN, 72: 9.0 P), 6.85 (9, VN, 12 9.0 Hz), 6.40 (4, IN, 12: 8.2 Hyd), 5, 39 (4, i z» in, 7.1 Hz), 3.81 (5, 6H), 3.78 (5, 6H); LC/MS: retention time: 32.76 minutes; purity: 9595; MS (mass/charge: 581 (МН. 73418 К935005: М2,М4-bisdiphenylmethyl)-5- Analogous to the preparation of М2,Ма4-bis(3-hydroxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine pyrimidinediamine, M2, Ma-bisidiphenylmethyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 1,1-diphenylmethylamine and 7,4-dichloro-5-(ee) fluoropyrimidine. IN NMR (SOSIZU: 2 7.91 (d, IN, 1- 2.3 Gy), 7.39-7.25 (t, 20H), 6.51 (4.1H, 7- 8.2 Gy) . MO M4-bisy li-(4- Analogously to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4- - chlorophenyl)methyl|-5-fluoro-2,4- pyrimidinediamine, M2,M4- bis(di-4(4-chlorophenyl)methyl|-5-fluoro-2,4-pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of benzhydrylamine and 2,4-dichloro-5-fluoropyrimyline. other and - (Ce) (42) ko 60 b5

IN NMR (SOSIZ -SOoZOoru s 7.944, 1, 12 2.3 Hz), 7.40-7.20 (t, 16Н), 6.46 (y,

IN, - 8.2 Gy), 5.69 (y, IN, /- 7.0 Hzu; LC/MS: retention time: 32.83 minutes; purity: 9099; MO (mass/charge): 599 (MNK ). pyrimidinediamine, M2,M4-bis|1(8)-4-methoxyphenylethyl)-5-bromo-2,4-pyrimidinamic pyrimidineamine is obtained as a result of the reaction of (K)-(k)-1-(4-methoxyphenyl)ethylamine and 5 -bromo-2,4-dichloropyrimidine. N YAM? (SOSIZ): 2 7.81 (5, 18), 7.25 (9, ZN, 72: 8.4 Go), 6.86 (arr. 5 JAN, 1- 8.4 and 8.7 Hz), 5.27-5.20 t (2H), 5.09 (da, IN, 7 6.4 and 7.0 Hz), 4.89 (ad, IN, 1- 6.4 and 7.0 Gy) ), 3.80 (5, ZN), 3.79 (z, ZN), 1.40 (4, 6H, 1-7.0 Gy). 7-3.121 K935075: 42, MA-bisG3-(2- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-hydroxyethoxy)phenyl|-5-fluoro-2,4-pyrimidinediamine, I42,M4-bis|3-(2-hydroxyethoxy)phenyl|-5-fluoro-2,4-pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 2-(3-aminophenoxy)stanol. IN NMR (OMO-46): P 9.50 (Be z, 1NU, 9.35 (g 5, 18), vls(a1H,1- 4.1 Sy), 7.44 (9, 1, 35 7.6 Hz), 7.26-7.19 (t, 4NU, 7.10 (5, 1, 25 7.6

Hz), 6.65 (44, 1H, 1- 2.3 and 8.2 Hz), 6.50 (04, IN, 72.3 and 8.2 Hz), 5.0 (bg 5, 2H) ), 3.91 (6 2H, 1- 5.2 Gu), 3.85 (i, 2H, 1- 5.2 Hz), 3.68 (od, 2H, 1-- 5.2. Hz) , 3.66 (di, 2H, 2 5.2

Hn); LC/MS: retention time: 15.76 minutes; purity: 9790; MS (mass/charge): 401 (MNU. 7.3.122 k935076: M2,ma-bis(3-(2- Analogous to the preparation of M2,Mma4-bis(3-hydroxyphenyl)-5-fluoro-2,4- 75 methoxyethyl )oxyphenyl|-5-fluoro-2,4-pyrimidinediamine, M2,M4-bis(3-(2-methoxystyl)oxyphenyl)-5-fluoro-2,4-pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro- of z-fluoropyrimidine and 3-(2-methoxyethoxy)aniline. IN NMR (SOSIS): C 7.96 (y, 1H, 12 2.9 Hz), 7.36 (B 1H, 121.7 Hz), 7, 28 (IN 1.7 Hz), 7.25-7.06 (t, 4H), 6.98 (bg 8, 1NU, 6.75 (4, 1H, 1-5 2.3 g), 6, 70 (44, 1H, 1- 1.7 and 8.2 Hz), 6.58 (94, 19, 3- 1.7 and 8.2 Gy), 4.08-4.03 (t, 4H) , 3.74-3.69 (t, 4H), 3.44 (5, ZN), 3.43 (5, ZN); LC/MS: retention time: 21.01 minutes; purity: 9795; MS ( mass/charge): 429 (MN). 7.3.123 K935077: M2.M4-bis(5-hydroxy-2" Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4- isopropylphenia) -5-fluoro-2,4-pyrimidinediamine, M2M4-bis(5-hydroxy-2-isopropylphenyl)-5-fluoro-2,4-pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 3-amino-4-isopropyl zero and 2.4. of dichloro-5-fluoropyrimidine, 1H NMR (SOSISU: Si 7.93 (0, 1H, re 3.5 Hz), 7.79 (g 5, 18), 7.64 (Bg5, 1H), 7.13 ( a, 1H, 24- 8.7 Go), 7.06 (a, 1H, 7- 2.3 Hz), 7.054, 1H, 1- 8.7

Hz), 6.89 (4, 1H, /e 2.3 Hz), 6.66 (4, 1H, T- 2.3 and 8.7 Hyd), 6.57 (4, 1H, 1- 2 ,3 and 8.7

Gy), 2.96 (t, 2H), 1.254, 6H, 1--7.0 Gy), 1.13 (dd, EN, 3 7.0 Gy); РЧ/ЛМС: length of stay; 24.27 minutes; purity: 9795; MC (mass/charge): 397 (MN). and. k935114: Mo, Ma-bis(3- Similar to the preparation of M2,M4-bis(3-hydroxyphenia)" 5"fluoro-2,4- o methoxycarbonylmethylenephenyl)-5-fluoro- | pyrimidinediamine, M2,M4-bis(3-methoxycarbonylmethylenephenyl)-5-fluoro-2,4-2,4-tyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-(methoxycarbonylmethylene)aniline. IN NMR (0M50-463: C 10.23 (bg 5, 1H), 10.05 (yg 5, 1NU, 8.26 (4, 1H, 3- 4.6 Gy), 7.64 (y, 1H , 1: 8.2 tsu, 7.51 (c 5, 1), 7.46 (y, IN, "se

B-8.2 Hz), 7.33 (y 5, 1H), 7.29 (5 IN, 17.6 Gy), 7.20 (6 1H, 1-5 7.6 Go), 7.064, 1H, 127 ,6 Gy), 6.93 (4, 1H, 3-: 7.6 Gy), 3.63 (5, 2), 3.58 (5, ZH), 3.57 (5, ZNU, 3, 56 (5, 7H);

LC/MS: retention time: 21.74 minutes; purity: 9295; MS (mass/charge): 425 (e) (MNu. 7.3.4125 8935162: M2, Ma-bis(3,4- Similar to the preparation of M2,M4-bis(3-tihydroxyphenyl)-5-fluoro-2,4- ach propylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine, M2,M4-bis(3,4-propylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-pheorotyrimidine and sem (3,4-propypenedioxyaniline. IN NMR (0M50-d6): 29.8 (5, IN), 9.7 (5, IN), 8.3 (a, 1H, 1-3, Hn), 7, 8 (04, IN, 3 2, and 8, Hz), 7.5 (0, 15, Ie 2, Hzu, 7.3 (4, 1H, 2-2, Go), so 7.8 (ad, 1H, 2-2, and 8, Hz), 6.0 (d, 1H, 1-8, Pi), 6.08, 1H, 3-8, Gy), 4.1-3.8 (t, 88), 2.09-2.01 (t, 4H)); LC/MS: retention time: 21.40 minutes; purity: 9795; MS (mass/charge: 425 (MY.Yu). 7.3.4126 K935163 : M2,M4-bis(3-chloro-4- Analogous to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-fluorophenyl)-2,4-pyrimidinediamine pyrimidinediamine, M2, M4A-bis( 3-chloro-4-fluorophenyl)-2,4-pyrimidinediamine " is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline. 1H NMR (OM 50 -46): 179.58 (in, 1H), 9.48 (5, 1H), 8.17 (4, 1H, 2241

Ty), 7.94-7.90 (t, 2), 7.73-7.67 (t, NU, 7.51-7.45 (t, NN), 7.38 (, 1H, 2- 88 Gy), wsh 7.26 (61.2-8.8 Hz); LC/MS: retention time: 27.53 minutes; purity: 9995; s MS (mass/charge): 386 (MN-Y), h 7.3.127 М2,Ма4-bis(3-hydroxyphenyl)-6- Similar to the preparation of М2,М4-bis(3-hydroxyphenyl)-5-fluoro-2,4- and » ethoxycarbonyl-5-nitro-72,4- pyrimidinediamine, M2,M4-bis(3-hydroxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine (KU25849) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-b-ethoxycarbonyl-5-nitropyrimidine and 3- aminophenol. IN NMR (0М50-46); (1 10.56 (55, НУ, 10.32 (р8, 1Н), 9.54 (5, 1Н), 9.32 (65, 1НУ, 7.22- 7.15 (t, 2H), 7.02-6.96 (t, IN), 6.93-6.82 (t, 2H), 6.81-6.74 (gl, 1H), 6, 67 (4, 1H, 7-93 Gy), 6.43 (6, 1H, 2- 8.1 Hz), 4.35 (4, (ee) 2H, - 6.9 Gy), 1.30 ( and, ZN, 7- 6.9 Hz); LC/MS: retention time: 26.01 minutes; purity; 96 55; MO (mass/charge): 412 (MNK). ko 7.3.128 M2,M4-bis (3,4-ethylenedioxyphenyl)-6- Similarly to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2, 4-Ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine, IM2,M4-bis(3,4-styrenedioxyphenyl)-b-ethoxycarbonyl-5-nitro-2,4- pyrimidinediamine (5925852) pyrimidinediamine is obtained as a result of the reaction 2,4-lichloro-6-ethoxycarbonium-5-nitropyrimidine and 3,4-styrenedioxyaniline. IN NMR (0M50-46): GI 10.52 (5, 18), (Se) (42) ko 60 b5

10.28 (5, 1H, 7.07-7.01 (t, 7H), 6.96 (84, IN, /- 1.8 and 8.7 Gy), 6.90-6.84 (t , 2H), 6.61 (0, 1H, 1- 8.7 Ha), 4.33 (4, 7H, 1: 6.9 Hyd), 4.24 (in, 4H), 4.17 (z, 4H ), 1.29 (i, ZN, 1- 6.9 Gy); RZHUMS: duration of retention: 30.40 minutes; purity: 100 95; MS (mass/mass): 496 (MN). 7.3.129 M2, Ma-bis(ethoxycarbonylmethia)-6- Similar to the preparation of M2,Ma-bis(3-hydroxyphenyl)-5-fluoro-2,4- and ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine, M2,M4-bis( ethoxycarbonylmethyl)-b-stoxycarbonyl-5-nitro-2,4-pyrimidinediamine (2925864) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-b-ethoxycarbonyl-5-nitropyrimidine and glycine ethyl ether hydrochloride with the addition of triethylamine. : a mixture of GI rotamers 8.99 and 8.80 (255, 1H), 6.22 and 6.00 (265, 1H), 445 2H,1-7.2 Gy), 4.31-4.21 (t , 6H), 2.14 (4, 2H, 31-5.1 Hz), 1.39 (6 ЗН, 17.2 Gy), 1.34-1.28 (t, 6H); LC/MS: retention time: 26.06 minutes; purity: 99 95; MS (mass/charge): 400 (MN). 7.3.130 М2,Ма4-bis(2-(4-hydroxyphenyl)ethyl|-2,4- | Analogously to the preparation of М2,М4-bis(3-hydroxyphenyl)-5-fluoro-2,8-pyrimidinediamine (KU25799) pyrimidinediamiva . IN), 9.23 (v, 13, 8.89 (55, 14), 7.92 (v5. 18), 7.60 (0, 1H, 1-6.9 Hz), 5.99 (a , 4H, 7-: 8.1 Gy), 6.65 (0, 4H, 2: 8.1 Go), 6.00 (4, 18, 3 7.2 Hz), 3.59-3.42 (t, 4H), 2.76-72.67 (tv, 4H); LC/MS: retention time: 17.93 minutes; purity: 95 25; MS (mass/charge): 351 (MN). 7.3. 131 2,m4-bis(2-phenylphenyl)-2,4- Similar to the preparation of M2,m4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (K925804) pyrnimidinediamine, M2,M4-bis(2 -phenylphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-lichloropyrimidine and 2-aminobiphenyl. IN NMR (SOS: 7 5.36 (b, IN, 1-2 8.1 0), 7.97 ( 4, 1H, 1 5.7 Gy), 7.804, 1H, 3 7.5 Hz), 7.350-7.21 (t, 15H), 7.12-7.05 (t, 1H), 6.91 ( c, 1), 6.38 (b, 10), 6.07 (9, IN, and: 6.0 Hz); RHUMS: retention time: 29.94 minutes; purity: 100 95; MS (mass/grind): 415 (MIN). 73.132 M2,M4-bis(2-methoxy-5-phenylphenyl)-2,4- | Analogously to the preparation of M2.h4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (K925805) pyrimidinediamine, M2,M4-bis(2-methoxy-5-phenylphenyl)-2,4-pyrimidinediamine is obtained as a result reactions of 2,4-dichloropyrimidine and 5-phenyl-ortho-anisidine.

IN NMR (SOZOPYU); C 7.88-7.84 (t, 20), 7.82 (b, IN, 7-69 Gy), 7.30-7.14 (t, 148), 7.10 (j, OH, 2 3.0 and 8.1 Go), 6484, 1 H, 12 6.9 Gy), 3.93 (5, ЗН). 3.92 (5, ZN);

LC/MS: retention time: 30.09 minutes; purity: 94 90; MC (mass/charge): 476 (MN). 7.3.133 М2,Ма4-bis(3-carboxy-4-tihydroxyphenyl)»- Similar to preparation 2,М4-bis(3-hydroxyphenyl)-5-fluoro»2,4- Ha! 5-fluoro-2,4-pyrimidinediamine (K945041) of pyrimidinediamine, M2,M4-bis(3-carboxy-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine (235 mg, 9895) is obtained as a result of the reaction of 5- amino-2-o hydroxybenzoic acid (458 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol). IN NMR (0М5О0-46): О 6.76 (4, 1- 9.9 Hz, 1 NO), 6.88 (8, 3-96 Hz, 1

H), 7.75 (ad, 1 3.0,9.0 Gy, 1 NU, 7.90-7.94 (t, With NU, 8.02 (y, 2- 3.9 Hz, 1 H ), 9.04 (5, 1 NN. MH), 9.28 (5. 1 H, MH); 19E NMR (282 MG, OMB5O-yb): 7 -165.79; EX (liquid chromatography): 16 .02 minutes, 86.8295; M5 (t/x: 400.94 (MN). (se) 7.31134 Mo, ma -bis(4-methoxy-3-phenylphenia)-2,4- | Similar to the preparation of M2.IM4 -bis(3-hydroxyphenia)-5-fluoro-2,4-pyrimidinediamine (KO25806) of pyrimidinediamine, M2,M4-bis(4-methoxy-3-phenylphenyl)-2,4-pyrimidinediamine (22) is obtained as a result of reaction 2 ,4-dichloropyrimidine and 3-pheny-para-anisidine hydrochloride with the addition of triethylamine. IN NMR (SPPZOI): 21 7.93 (8, or 1H, 2-24 Gy), 7.88 (9, 1H, 12: 2, 4 Hz), 7.29 (44, 1H, 7-1.8 and 9.0 Gy), 7.26-7.18 (t, 138), 7.109, ZN, 1: 8.7 Gy), 6.56 (4, 1H, 12: 7.2 Hz), 3.93 (5, ZNU, 3.92 (5, ZN); s

LC/MS: retention time: 29.99 minutes; purity: 92; MS (mass/charge): 476 (Mn. so 7.3.135 M2,MA-bis(2-methyp-5-phenylphenyl)-2,4- Analogous to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro -2,4-pyrimidinediamine (KU25807) pyrnmidinliamine, M2,IM4-bis(2-methyl-5-phenylphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloropyrimyline and 5-phenyl-ortho-toluidine.

IN' NMR (PM50-46): HI 10.45 (Bv, IN), 10.01 (bv, EN), 7.86 (b8, 1H), 7.69-7.22 (c, 17), 2.28 (5, 6H); LC/MS: retention time: 18.69 minutes; purity: 98 25; "

MS (mass/charge) in: 443 (MN). 7.3.136 M2,M4-bi(2-methoxy-Z-methyp-4- Analogous to the preparation of 12, M4-bis(Z-hydroxypheny)-5-fluoro-2,4-in phenylphenyl)-2,4-nyrimidinediamine of pyrimidinediamine . . IN NMR (OM 50-46): P 9.99 (Bv, 18), 9.22 (vv, 18), "from 7.984, 1H, 2-6.3 Hz), 7.75 (8, 1H) , 7.59 (5, IN), 7.46-7.29 (t, TON), 6.92 (5, 18), i 6.87 (5, 13), 6.494, IN, 3» 5, 4 Gy), 3.82 (8, ZN), 3.81 (in, ZN), 2.07 (5, ZN), 1.98 (5,

ZNU; LC/MS: retention time: 19.69 minutes; purity: 93 25; MC (mass/charge): 503 (MN). |73437 Damn it. Similarly to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-(ee) (ethoxycarbonylmethyleneoxy)phenyl|-5-pyrimidinediamine, M2,M4-bis(4-(ethoxycarbonylmethyleneoxyphenyl|-5- trifluoromethyl- 2 4-pyrimidinediamine trifluoromethyl-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-co (8925862) trifluoromethylpyrimidine and ethyl-4-aminophenoxyacetate. IN NMR (0М5О-46); 7 9.64 (Л5, 1H), 8.50 (b5, 1), 8.29 (5, 1H), 7.36 (d, 2H, 5-8.1 Hz), 7.31 (d, 2H, 3-93

Sv), 6.93 (8, 2H, 1: 8.7 Gy), 6.70 (4, 2H, 1 9.0 Hz), 4.80 (5, NU, 4.67 (8, 2H) , 4.18 (8. - 2H,1- 6.9 Hz), 4.15 (4, 2H, 1-- 6.9 Hz), 1.20 (I, ZM, 1: 6.9 Hn) .

22210000 revom vv yuvmnia 7.3.138 M2,M4-bis(3-hydroxyphenyl)-5- Similar to the preparation of M2,M4-bis(3-tihydroxyphenyl)-5-fluoro-2,4" trifluoromethyl-2,4-pyrimidinediamine pyrimidinediamine, M2,M4-bis(3-tihydroxyphenyl)-5-trifluoromethyl-2,4- (9725863) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-trifluoromethylpyrimidine and 3-aminophenol. IN NMR (0M50-46: Gy 9.82 (B5, 1H), 8.88 (ie, IN, 8.36 (5, IN), 7.18-7.11 (t, 2H), 6.96 (t, 4H)), 6.63 (44, 1H, 1 2.4 and 8.1

ГИ), 6.38 (y, IN, /-: 8.1 Hz; I9E NMR (0M50-46y: 16979; LC/MS: retention time: 19.04 minutes; purity: 95 95; MS (mass/charge): 363 (INN). 7.3.139 M2,m4-bisr4- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-(ethoxycarbonylmethyl)phenyl|-5-pyrimidinediamine, M2,M4-bis (4-(Ethoxycarbonylmethyl)phenyl-5-trifluoromethyl-2,4-trifluoromethyl-2,4-pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-(K926663) trifluoromethylpyrimidine and ethyl-4-aminophenine acetate. IN NMR ( SAUSAGE; C 8.31 (5. 1H), 7.46 (a, 2H, 3 9.0 Gy), 7.45 (0, 2H, 1- 8.7 Gy), 7.304, 2H, 19.0 Hz), 7.18 (a, 2H, 1,807 Ha), 7.16 (05, 1NI), 6.82 (65, IN), 4.16 (29.4H,1- 7.8 Gy), 3.64 (5, 2H), 3.57 (8, 2H), 1.276 ZN, 17.8 Hz), 1.266 ZN, 1- 7.8 Hn); 19E NMR (SOSISU: - 17223; LC/MS: retention time: 28.07 minutes; purity: 99,955; MS (mass/charge): 504 (MN). 7.3.140 M2,M4-bis(2,5-dimethyl-4-hydroxyphenyl)- | Similar to the preparation of M2, M4-bis(3-hydroxyphenia)-5-fluoro-2,4-5-fluoro-2,4-pyrimidinyldiamine (K926623) of pyrimidinediamine, M2,M4-bis(2,5-dimethyl-4-hydroxyphenyl)-5-fluoro-2,4- pyrmidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 2,5- dimethyl-4-tihydroxyaniline. IN NMR (UNION): 2 7.63 (4, 1H, 14.2 Hz), 7.05 (5, 1H), 6.97 (5, 13), 6.64 (1), 6.54 ( 5, 1H), 2.12 (5, NO), 2.06 (5, ZNI), 2.03 (5, ZN), 2.03 (5, ZN); and 9E NMR (SVZOYO): -48488; РХ/MS: retention time: 18.28; purity; 9495; MC (mass/charge): 369 (MN). 7.3.4141 M2,M4-bis(3-sodiumphenoxy)-5-fluoro-2,4- | M2/M4-bis(3-sodiumphenoxy)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of pyrimidinediamine (K926451) reaction of 142244-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine and 2 equivalents of methylate of sodium in methacol after removal of the solvent, 1H NMR (020): and 7.65 (Ba, 1H), 7.00-6.90 (t, 2H), 6.71 (t, 2H), 5.55 (49 , 1H, 1- 1.2 and 6.3 Go), 6.31 (64,

IN. 1: 8.1 Gy)u, 6.23 (6.1H, 1-8.7 Gy); 19E NMR (020): -47016; РЧ/МС: duration of retention; 15.58 minutes; purity: 9975; MS (mass/charge); 313 (MENU). 7.3.142 M2,M4-bis(3-cyanophenyl)-5-fluoro-2.4- Similar to the preparation of IM2,44-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinidiamine (K945051) pyrimidinediamine, M2,M4 -bis(3-cyanophenyl)-5-fluoro-2,4-pyrimidinidiamine (75 mg, Ga 7695) is obtained as a result of the reaction of 3-aminobenzonitrile (177 me, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol). IN YAM (acetone-9b): :: 7.33 (4, o 1-1.8,7.8 Hz, I NU, 7.46-7.52 (t, 2 1), 7.59 (i . H), 8.174, 123.31, 1 H), 81 (t, 1), 8.35 722, Hy, 1 NO), 8.98 (be, 1 H, MH), 9.02 (lg, 1 H, MN); 19E YM (282

MG, acetone-ydb): Pi -165.80; LC/MS: 24.64 minutes; purity: 98.0294; MS (mass/charge): 331.01 (MN). se 7.3.143 M2,M4-bisibenzothiophen-3-ylmethyl)-5- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (8945145) pyrimidinediamine, M2,M4-bis(benzothiophen-3-ylmethyl)-5-fluoro-2,4-pyrimidinediamine (e") is obtained as a result of the reaction of benzothiophen-3-ylmethylamine and 2,4-dichloro-5-fluoropyrimidine. 1H NMR (SOSIS): 0 4.82 (4d, 1- 0.9 and 5.7 Hz, 2 H), 4.86 (44, 1- 0.9 and 5.7 Gy, 2 NU, 5, 14 (bg, 2 NU, 7.31-7.40 (t, 6 H), 7.75-7.89 (t, 5 NU; 192 YAM? -- (282 MHz, SOSIZU: 0 -172.12 ; LC/MS: 27.79 minutes; purity: 96.47; MS (mass/charge): 420.92 (MN). se 7.3.144 M2,m4-bisI4-4(0M- Analogous to the preparation of M2,h4- bis(3-hydroxyphenyl)-5-fluoro-2,4-

Benzylpiperazino)phenyl|-5-fluoro-2,4-pyrimidinediamine, M2,M4-bis/4-(M-benzylpiperazino)phenyl|-5-fluoro-2,4-he)pyrimidinediamine (KO45152) pyrimidinediamine (120 mg , 6495) are obtained as a result of the reaction of 4-O4-benzylpiperazino)aniline (400 mg, 1.5 mmol) and 2,4-dichloro-3-fluoropyrimidine (50 mg, 0.3 mmol). 1H NMR (SRS): 7 2.63 (p, 222.4 Hz, 8 H), 3.14 (,7:4.8 Hz, 4 NU, 3.19 (,2- 4.8 Ho, 4 H), 3.58 (5, 4 H), 6.58 (y, 1 Y, MH), 6.67 (Be, I H, MH), 6.87 (d, z- 9.3 Gy, 2 NU, 6.90 (4, 1-:9.0 Gd, 2 NO), 7.33-7.39 (t, 12. NU, 7.46 (4, 2- 9.0 Hn, 2 H ), « 7.874, 12 3.3 Hz, 1 N); 192 NMR (282 MHz, SOSIS): P -169.06; LC/MS: 16.82 minutes; purity: 96.8895; MS (mass/charge ): 629.12 (MNK). - 7.3.145 M2,Ma-bis(3-hydroxy-2-methylphenyl)-5- Similar to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4 - c fluoro-2,4-pyrimidinediamine (5945038) of pyrimidinediamine, M2,M4-bis(3-hydroxy-2-methylphenyl)-5-fluoro-24-pyrimidinediamine (180 mg, 8895) is obtained as a result of the reaction of 3-hydroxy- 7- in!z» methylaniline (369 mg, 3 μmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol). 1H NMR (apeton-46): 0 2.14 (5, 3 H), 2.22 (5, 3 H), 6.61 (dz V g, 1 NU, 6.78 (51-87 Hz, 1 H), 6.87 (b, 1- 7.8 Hz, 1 H), 6.99 (4, 22: 9.0 Hz, 1 NU, 7.08 0, 1-5 7.8

Hz,1 NO), 7.13 (44, 7-5 3.9, 8.4 Hz, 1 Nu), 8.24 (0, 2 5 Su, 1 H), 8.32 (Tu, 1 H, MH ), 8.57 (Bg, ! H, MNU, RH/MS: retention time: 16.51 minutes; purity: 90.4795; bo MS (mass/charge): 341.07 (MNE). 7.3.146 M2 ,M4-bis-nitrophenyl)-5-fluoro-2,4-2,4-dichloro-5-fluoropyrimidine (4.7 g, 28.1 mmol) is dissolved in a mixture of MEeOH (150 co pyrimidinediamine (KU50160) ml) and H2O (15 ml). 3-Nitroaniline (15.5 g, 112 mmol) was added to the mixture and heated in a reflux flask for 20 hours (oil bath temperature -100°C). Next, the mixture is cooled to 220C and filtered. shk The residue is carefully washed in 200 ml of MEOH-H2O solution (1:1 by volume) and dried in a vacuum. As a result, 7.89 g (7690) of M2,M4-bis(3- (Ce) (42) co 60 b5 nitrophenyl)-5-fluoro-2,4-pyrimidinediamine are obtained in the form of yellow crystals. IN

YAM (0M50-46 -- 220): (Z 8.63 (t, 2), 8.21 (lo, 18), 8.08 (4, 1H,, 12 8.44 Gi), 7.88 ( 9, 18, 2-84 Si), 7.794, 1H, 7-2 85.4 Gy), 7.70 (d, 1, 12 8.4 Ha), 7.574, 1H, 1284

Hzu 7.45 1H, 3-8.4 Gy); LC/MS: purity: 10025; MS (mass/weight): 371.30 (M, 100). 9 7.3.147 M2,M4-bis(3-aminophenyl)-5-fluoro-2,4- M2M4-bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine (4.0 g, 10.8 mmol) and 1092-pyrimidinediamine (K92 1302) ny PO/C (1.2 g, contains 5095 water) are placed in the form of a suspension in 300 ml of EYN-1090 aqueous solution of NS (1: them) and hydrogenated in a Parr apparatus for 6 hours (220, 3.4 atm). The resulting suspension is filtered through celite and carefully washed in 20 ml of DMF-H2O solution (1:1 by volume), and then in 50 ml of H2O,

The collected filtrates are concentrated under reduced pressure to a pale yellow oil, which is then triturated with MeOH to obtain a product in the form of fine white needles. The residue is filtered and washed first with MeOH solution and then with E2O solution. The remaining crystals are dried in vacuo to give 4.00 g of pure material (10096) according to LC/MS analysis. The free amine is obtained by adding 100 ml!M

Mahon to a solution of the salt of NSI in 5 ml of H2O. The resulting precipitate is filtered, washed with water and dried under vacuum for 74 hours to obtain M2,M4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidineliamine (770 mg)

In the form of a white solid fraction. IN NMR (COSO): С 7.924, 1Н, 12 3.6

Gsh),7.31( IN, In Hz), 7211 N, 1-24 tsu, 7.08, (6 IN, 1 8.1 Hz), 6.99 1H, 1- V Gy), 6.88 (t, 18), 6.77 (t, NN), 6.47 (t, IN), 6.34 (t, IN); LC/MS: purity: 10095; MS (mass/charge): 311.07 (ME, 100). 7.3148 2, M4-bis(4-aminophenyl)-5-fluoro-2,4- Similar to the preparation of M2,M4-bis(3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine, pyrimidinediamine (K950122) 7M2,M4 -bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 1,4-diaminobenzene. ВХ/МС: retention time: 11.15 minutes; purity: 10095; MS (mass/charge): 311.09 "MNK. 7.31149 72, M4-bis3-(dimethylamino)phenyl|-5-2,4-dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) is dissolved in a mixture of MeEOH (0.3 fluoro-2,4-pyrimidinediamine (59501872 ) ml) and H2O (0.03 ml). MM-3-Dimethiadiaminoaniline (163 mg, 1.2 mmol) was added to the mixture and heated in a reflux flask for 24 hours (oil bath temperature: 70°C). After fermentation, the mixture is cooled to 220C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-acetone, 2:1) in order to obtain M2,M4- bis 3-(dimethylamino)phenyl|-5-fluoro-2 ,4-pyrimidinediamine. LC/MS purity: 99.09; everything

MS (mass/charge): 367.13 (M, 100). 7.341150 M2,MA-bis(3-amico-4-methylphenyl)-2,4-2,4-diporpyrimidine (45 mg, 0.30 mmol) is dissolved in a mixture of MeOH (1 ml) and pyrimidinediamine (K950130) H2HO (0 ,1 ml). 3-Amino-4-methylaniline (146 mg, 1.2 mmol) was added to the mixture and heated in a reflux flask for 20 hours (oil bath temperature: 70°C). After that, the mixture is cooled to 220°C, concentrated to dryness under reduced pressure, and subjected to carbon chromatography on (Che) silica gel (CHCl-acetone, 2:1) in order to obtain M?,M4-bis(3-amino-4-methylphenyl) -2,4-pyrimidinlyamine. IN NMR (SOZOUU; 0 8.13 (5, 1H), 6.95 (y, 2H,

T-7.5 Hz), 6.82 (4, 2H, 1- 1.8 Hz), 6.60 (09, 2H, 1- 1.8, 7.5 Go), 6.17 (5, 18), 2.12 (z, b» 6H); LC/MS purity: 97.395; MS (mass/charge): 321.09 (M'zh, 100). 73451 2 M4-bis(3-amino-4-methylphenyl)-5-2,4-dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) is dissolved in a mixture of MEON (1-fluoro-2,4-pyrimylidenediamine ( K950129) mya) and H2O (0.1 ml). 33-amino-4-methylaniline (146 mg, 1.2 mmol) was added to the mixture and heated in a reflux flask for 20 h (oil bath temperature: 70 92). After that, the mixture is cooled to 220C, concentrated to dryness under reduced pressure and subjected to column (ee) chromatography on silica gel (SNCI3-acetov, 2: I) in order to obtain M2,M4-bis(3-amino-4-methylphenyl) -5-fluoro-2,4-pyrimidinediamine. IN NMR (SOZOI): 818.1, 2-51 Hz), 7.98 (65, 1) (7.68 (ai, IN, )- 2.4, 8.1 Hz), 7.40-7 .55 (tb, 4H), 2.43 (in, ЗН)), 2.42 (in, ЗН); LC/MS: purity: 95.04; MS (mass/charge): 338.66 (MA, 70u. « 7.3.152 142.M4-bis|(4-methylsulfonylamino-2.4-dichloro-5-fluoropyrimidine) (50 mg, 0.30 mmol) is dissolved in a mixture of MeOH (1 )phenyl|-5-fluoro-2,4-pyrimidinediamine ml) and H2O (0.1 ml). 4-Methylsulfonylaminesaninine (335 ml, 1.8 mmol) was poured into a w-v (K950083) mixture and heated in flask with a reflux condenser for 74 hours (oil bath temperature: 1000C).After that, the mixture is cooled to 220C.

The residue is carefully washed with a Meon-H2H0 solution (1:1) and dried under vacuum to obtain M2,M4-bis!(4-methylsulfonylamic)phenyl|-5-fluoro-2,4-p» pyrimidinediamine. TYA NMR (SOSIS): 0 8.86 (5, 1H), 8.65 (5, 1H), 8.53 (5, IN), 8.39 (b, 1H), 7.324, IN, 1: 3 ,3 Hz), 7.12 (4, IN, 7- 8.7 Gy), 6.98 (6, IN, 1: 8.7 Hz), 6.62 (F 18, 18.7 Hz), 6.524. (M, 100). About 7.3.153 m2, M4-bis(4-benzyloxy-3-2,4-dichloro-5-fluoropyrimidine (50 me, 0.30 mmol) is dissolved in a mixture of MeOH (I trifluoromethidphenyl)-5 -fluoro-2.4-ml) and H2O (0.1 ml). 4-Benzyloxy-3-trifluoromethaniline (481 me, 1.8 mmol) pyrimidinediamine (K950090) was added to the mixture and heated in a reflux flask for 7 ke days (oil bath temperature: 70007). Then the mixture is cooled to 220, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (SNCI3-acetone, 9:1) in order to obtain IM2,Ma4-bis(4-20 benzyloxy-3-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine, IN NMR (Ce) (42) ko 60 b5

(SRSI3U: 0 8.51 (5, 1H), 8.05 (5, 1H), 7.38-7.64 (t, 5H), 6.94-7.14 (t, 11 H), 6 ,44. 6.73 (t, 4H), 4.84 (5, 2H), 4.79 (5, 2H); LC/MS purity: 94.795, MS (mass/charge): 628.93 (M, 100). 73454 Mo ma-bis(3-cynan-4-hydroxyphenyl)-5" 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) is dissolved in a mixture of MeOH (1 fluoro-2,4- pyrimidinediamine (K950092) mL) and H2O (0.1 mL).3-Cyano-4-hydroxyaniline (241 mg, 1.8 mmol) was added to the mixture and heated in a reflux flask for 2 days (oil bath temperature: 700 ).After that, the mixture is cooled to 220C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-acetone, 9:1) in order to obtain M2,M4-bis(4-hydroxy-3-cyanophenyl)-5 -fluoro-2,4-pyrimidinediamine.

IN, - 3.5 Hz), 7.82 (d, IN, 2: 3.0 Go), 7.79 (A, IN, 7-: 3.0 Hz), 7.71 (da, 1H, 2: 30, 8.8 Ha), 7.54 (ad, 1-2 3.0, 8.8 Gy), 6.944, IN, 7 8.8 Hz), 6.84 (а, 1Н, 7- 8.8 Hz);

LC/MS: purity: 97.25; MS (mass/mass: 362.98 (MA, 100). 7.3.155 Mo M4-bis3-2,4 dichloro-5-fluoropyrimidine (50 me, 0.3 mmol) is dissolved in a mixture of MeOH (1 ml) methylsulfonylamino) phenyl|-5-fluoro- and H2O (0.1 ml). 3-Methylsulfonylaminoaniline (300 mg, 175 mmol) was added to the 2,4-pyrimidinediamine (KU50100) mixture and heated in a reflux flask for 24 hours (oil bath temperature: 7002). After that, the mixture is cooled to 220C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-acetone, 9:1) in order to obtain M2,M4-bis(/3-methylsulfonylamino)phenyl|-5-fluoro- 2,4-pyrimidinlyamine. 1H NMR (0M50-406

SOZOI): 2 8.01 (9, IN, 1- 3.5 Hz), 7.46-7.68 (t, 4H), 7.49 (i, IN, ze 8.2 Hz), 7, 13 0, 1H, 7-2 8.2 Ha), 6.89 (44, 1H, Be 2.4, 8.2 Sy), 6.72 (pz, 185), 2.95 (5, ZNU, 2.91 (5, ZN);

RHLIS: purity: 97.290; MS (mass/charge) in: 466.89 (Mk, 100). 73156 Ma, Ma-bis(3Z-(tert-2,4-dichloro-5-fluoropyrimidine (75 mg, 0.45 mmol)) is dissolved in a mixture of MeOH (2-butoxycarbonylamino)phenyl|-5-fluoro-ml) and H2O ( 0.2 mL).3-tert-butoxycarbonylaminoaniline (374 mg, 1.8 mmol) 2,4-pyrimidinediamine (KU50108) was added to the mixture and heated in a reflux flask for 40 hours (oil bath temperature: 700°C). Liesl this mixture is cooled to 22°C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-acetone, 9:1) in order to obtain M2,M4-bis(3-ytt-butoxycarbonylamino)pheny)-5-fluoro -2,4-pyrimidinediamine. IN NMR (pM50-y06 4 SOSO): 0 7.96 (0, 1H, 124.1 Hz), 7.83 (t, 18), 7.60 (t 1NU, 7.34-7.42 (t, 2H ), 7.15-7.19 (t, 2H), 7.06 and, 18, 1-8.2 Gy), 6.93 (9, 1H, 2- 8.2 Go), 1.43 ( 5, ZNU, 1.40 (5, UN); LC/MS: purity: 93.25; MS (mass/charge): 511.06 (Mk, 1003. Ha butoxycarbonylamino)phenyl|-5-Ffluoro-ml) and H2O (0.2 ml). 4-tert-butoxycarbonylaminoaniline (374 me, 1.8 mmol; Ge) 2,4-pyrimidinediamine (K950120) was added to the mixture and heated in a reflux flask for 24 hours (oil bath temperature: 700). After this sum: cooled to 220C, concentrated to dryness under reduced pressure and subjected to column chromatography on Silica gel (CHCl3-acetone, 9:1) in order to obtain M2,M4-bisy4-se (tert-butoxycarbonylamino)phenyl-5 -fluoro-2,4-pyrimidinediamine. IN NMR (0М8О0-46 i SOZOB): О 7.96 (y, IN, 1: 3.5 Hz), 7.63 (4, 2Н, 1-: 8.8 ГИ), 7.29 (d, 2H, 1-88 g), 7.37 (4, 2H, 3- 8.8 Hz), 7.24 (4, 2H, )- 8.8 ГИ), 1.45 (z, 9H), 1 .43 (5.9H); (22)

LC/MS: purity; 97,995; MS (mass/charge): 511.04 (Mk, 100). 7.3.158 Mm2,M4-bis(2-(2- M2,Ma-bis|2-(ethoxycarbonyl)-benzofuran-5-ylI-5-fluoro-2,4-pyrimidinediamine) (10 mg, h-(methylamino) ethyleneaminocarbonyl) - 0.02 mmol) is dissolved in EN, M-methyl-1,2-aminoethane (0.1 ml: 0.1 ml) benzofuran-5-1l|-5-fluoro-2,4- is added and heated sum in a flask with a reflux condenser for 3 days se pyrnmylindiamine (2950170) (oil bath temperature: 700). After that, the mixture is cooled to 220C, dissolved in water and filtered. The residue is subjected to column chromatography on so silica gel (SNCI3-acetone, 2:1) 3 in order to obtain M2,M4-bis(2-(2- (methylamino)hethyleneaminocarbonyl|-benzofuran-5-yl|-5-fluoro-2,4-pyrimidinediamine). IN NMR (0M50-46 4 SOZOrU; 2) 8, 14 (5, IN), 8.02 (5, 1NU, 7.99 (8, 1H, 7-24 Hyd), 7.35-7.68 (t, 5H), 7.17 (5, 1H) U, 3.41 (t, 2H), 2.75 (t, 2H, 2.35 (5,

ZNU); LC/MS: purity: 84.25; MS (mass/charge): 561.08 (Mk, 190). « 7.3.159 2, Ch4-b16 (2422- Similar to the preparation of M2, M4-bis(2-(2-(methylamino)ethyleneaminocarbonyl|- hydroxyethyleneaminocarbonyl)-benzofuran-5-yl)-5-fluoro-2,4-pyramidinediamine . pyrimidinedismine (2950167) is obtained as a result of the reaction of M2,M4-bis|2ethoxycarbonide)-benzofuran-5-1l|-5-fluoro-2,4-pyrimidinediamine and 2-aminoethanol.. LC/MS: retention time: n » 14, 22 minutes, purity: 95.79, MS (mass/charge): 535.01 (MNK). |- aminoacetyleneaminocarbonyl)-benzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, M2,44-5is|2-(2-benzofuran-5-yl|-5-fluoro-2.,4- aminoacetyleneaminocarbonyl )-benzofuran-5-1l|-5-fluoro-2,4-pyrimidinediamine pyrimidinediamine (4950168) is obtained as a result of reaction M2,M4-6bis|2-(ethoxycarbonyl)-benzofuran-5-yl)-5- (o e fluoro-2,4-pyrimidinediamine and 1,2-diaminostane. LC/MS: holding time: 13.15 minutes; purity: 95.80; MC (mass/charge): 532.99 (MN). ko 7.3151 Mm2,m4-bis(2-(2-(M- Analogously to the preparation of M2,M4-6bis(2412-(methylamino)ethyleneaminocarbonyl|- benzylamino)ethyleneaminocarbonyl)-benzofuran-5-ylI-5-fluoro-2,4 -pyrimidinediamine, 142, M4-bisi2-(2-0M4--benzofuran-5-1l|-5-fluoro-2,4- benzylamino)ethyleneaminocarbonyl)-benzofuran-5-1l|-5-fluoro-2,4 -pyrimidinediamine pyrimidinediamine (K950169) is obtained as a result of the reaction of M2,M4-bis/2-(ethoxycarbonyl)-benzofuranez-ylI-5-se 50 fluoro-2,4-pyrimidinediamine and M-benzyl-1,2-diaminoethane. /MS: duration (42) of 60 b5 nin retention: 13.15 minutes; purity: 95.89; MS (mass/charge): 713.10 (MN). 7.3.162 M2,MaA-bisro-(M- Similarly to the preparation of M2,ich4-bis/2-12-(methylamino)styreneaminocarbonyl|-morpholinocarbonyl)benzofuran-5-yl)-5- | benzofuran-5-yl|-5-fluoro-2,4-pyrimidinediamine, M2.MA-bis(2-(M-fluoro-2,4-pyrimidinediamine (К950172) morpholinecarbonyl)benzofuran-5-yl|-5-fluoro -2,4-pyrimidinediamine is obtained as a result of the reaction of M2,M4-bis|2-(ethoxycarbonyl)-benzofuran-5-yl-5-fluoro-2,4-pyrimidinediamine and morpholine. C 8.13 (4, 1H, 12 2.7 i), 8.06 (8, IN, 2-24 Go), 8.03 (a, 1H, 3- 3.6 Hz), 7.63 ( yes, IN, 7: 2.4, 8.8 Gy), 7.57(0, IN, 19.3 Sc), 7.49 (yes, IN, 8-24, 8.4 Hn), 7.42 ( a, 1H, 15 8.8 Hz), 7.25 (5, 1H), 7.05 (5, IN), 4.09 (yah, 4NI), 3.65 (t, 4H); LC/MS: duration retention: 18.04 minutes; purity: 83.295; MS (mass/charge): 587.04 (MN). 7.3.163 1m2,M4-bis(242-M- Similar to the preparation of M2,M4-bis/2-(2 -(methylamino)ethyleneaminocarbonyl-morpholineethyleneaminocarboyl)-benzofuran-5-yl-5-fluoro-2,4-pyrimidinediamine, M2,M4-bis/2-(2-M-benzofuran-5-yl|-5-fluoro-2 ,4-morpholineethyleneaminocarbonyl)-benzofuran" 5-yl|-5-fluoro-2,4-pyrimidinediamine pyrimidinediamine (K950173) is obtained as a result of the reaction M2,M4-bis|2-( ethoxycarbonyl)-benzofuran-5-yl|-5-fluoro-2,4-pyrimidinediamine and H-(2-aminoacetylenamino)morpholine. IN NMR (0М50-а6 - СО3ОУУУ: Gy 8.16 (0, IN, 72 2.4 Hz), 8.03-8.05 (t, 2Н), 7.71 (44, IN, 1-2 1 .8, 8.8 Gnu, 7.56 (y, IN, 32 8.8), 7.42 (4, IN, 72: 8.8 1), 7.36 (5, 1H), 7.19 (5.18), 4.19 (t, 4H), 3.38 (t, 4), 3.16 (i, 2H, /- 6.3 Hz), 2.28 (, 2H, 1- 6 .3 Hz); LC/MS: retention time: 12.85 minutes; purity: 93.89; MS (mass/charge): 673.35 (MN. 7.3164 M2, Ma-bis(3-amino-4-nitrophenyl )-5-2,4-dichloro-5-fluoropyrimidine (50 mg, 03 mmol) is dissolved in a mixture of MeEOH (1 ml), fluoro-2,4-pyrimidinediamine (KU50135) and H2O (0.1 ml). -amino-4-nitroaniline (184 mg, 1.2 mmol) was added to the mixture and heated in a reflux flask for 3 days (oil bath temperature: 7003. After that, the mixture was cooled to 220 °C, concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (SNCI3-acetone, 9:1) in order to obtain M2,M4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. IN NMR (OM 50-46 - SOZOV): Z 8.21 (a 1H,2-2.9 Gy), 7.89 (t, Z), 7.56 (8, 1H, 22.3 Hz), 7.01 (i.e. 180), 6.81 (yes, IN, 1 2.3; 9.4 Gi); LC/MS: purity: 91.195; MS (mass/charge): 401.00 (M, 100). 7.3.165 M2, Ma-bis(3-amino-2,4-difluorophenyl)-5- | Similarly to the preparation of M2,M4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-fluoro-2.4A-pyrimidinediamine (K950138) pyrimidinediamine, M2,M4-bis(3-amino-2,4- difluorophenyl)-3-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-amino-2,4-difluoroaniline. LC/MS: retention time: 16.98 minutes; purity: 91.75; MS (mass/charge); 382.97 (MNK). sem (t o fluoro-2,4-pyrimidinediamine (К950139) pyrimidinediamine, M2,44-bis(3-amino-4-ethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro- of 5-fluoropyrimidine and 3-amino-4-ethoxyaniline. LC/MS: retention time: 14.29 minutes; purity: 93.4 MS (mass/charge: 399.09 (MH). 7.3.167 M2,M4-bis (3-amino-5- Analogous to the preparation of M2,M4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-(se)methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine, M2, M4-bis(3-amino-5-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (K950134) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and b

Z-amino-5-methoxycarbonylaniline. LC/MS: retention time: 14.72 minutes; purity: 93.895; MS (mass/gross): 427.02 (INN). 7.3.168 M2M4-bis(3-amino-5- Analogously to the preparation of M2,M4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4- - trifluoromethylphenia)-5-fluoro-2,4- pyrimidinediamine, I42,144-bis(3-amino-5-trifluoromethylphenyl)-5-fluoro-2,4-pyrimidinediamine (K950140) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and

Z-amino-5-trifluoromethylaniline. LC/MS: retention time: 23.35 minutes; purity: 10095; MS (mass/weight): 446.92 (MI). (ee) 7.31169 MO, M4-bis(3-amino-5-chlorophenyl)-5-fluoro- | Similarly to the preparation of M2,M4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-72,4-pyrimidinediamine (K950141) pyrimidinediamine, M2,Ma-bis(3-amino-5-chlorophenyl)- 5-fluoro-2,4-pyrimidinediamine is restrained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-amino-5-chloroaniline. LC/MS: retention time: 19.25 minutes; purity: 99.395; MS (mass/charge): 378.91 (MN). " 7.3.170 M2,MA.-bis(4-tihydroxy-3" Similar to the preparation of M2,M4-bis(3-amino-4-nitrophenyl-5-fluoro-2,4- chlorofluoromethylphenia)-5-fluoro-2, 4-pyrimidinediamine, M2,M4-bis(4-thiproxy-3-trifluoromethylphenyl)-5-fluoro-2,4- - pyrimidinediamine (2950093) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and a- tihydroxy-3-trifluoromethylaniline. LC/MS: retention time: 22.06 minutes; h purity: 99.192, MS (mass/charge)y: 448.88 (MNK). i » 734171 M2/M4-bis(3-aminophenyl )-5-fluoro-2,4- M2,m4-bis(3-aminophenyl)-5-fluoro-2,4-nyrimidinediamine is treated with two equivalents of pyrimidinedismine hydrochloride in dioxane. Volatile substances are removed under reduced pressure from (8950107 ) by the formation of 142, M4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine-hydrochloride salt. LC/MS: retention time: 9.74 minutes; purity: 91.390; MS (mass/charge): 311.06 (MH). 17.34172 M2,MA-bis(4-aminophenyl)-5-fluoro-2,4- M2,MA-bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine is treated with 2 equivalents pyrimidinediamine hydrogen chloride salt | NOSI in dioxane, Volatile substances are removed under reduced pressure with the formation of ko 8950121) M2, Ma-bis(4-aminophenyl)-5-fluoro-2,4-pyrimilindiamine-HCI salt. LC/MS: retention time: 11.15 minutes; purity: 10095; MC (mass/charge): 311.09 (MN). (Se) 42) ko 60 b5

7.3.173 M2,MA-bis(3-aminophenyl)-2,4- Similar to the preparation of IM2,M4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine (K950109) pyrimidinediamine, M2 ,M4-bis(3-aminophenyl)-2,4-pyrimidinediamine is restrained as a result of the reaction of 2,4-dichloropyrimidine and 3-aminoaniline. LC/MS: retention time: 8.90 minutes; purity: 9195; MS (mass/charge: 293.06 (MN). 7.34174 Mu M4-bis(3-amino-2,4-difluorophenyl)- Similar to the preparation of M2,M4-bis(3-amino-4-nitrophenyl)-5-fluoro -2,4- 2,4-pyrimidinediamine (KU50131) pyrimidinediamine, M2,M4-bis(3-amino-2,4-difluorophenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4 dichloropyrimidine and 3-amino- 2,4-difluoroaniline. LC/MS: retention time: 16.62 minutes; purity: 96.75; MS (mass/charge): 364.99 (MN). 7.3.175 M2,m4-bis(3-amino -4-ethoxyphenyl)-2,4- Analogous to the preparation of M2,M4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4- pyrimidinelimine (2950142) pyrimidinediamine, M2,M4-bis(3-amino -4-stoxyphenyl)-2,4-pyrimylinliamine is obtained as a result of the reaction of 2,4-dichloropyrimidine and 3-amino-4-ethoxyaniline.

LC/MS: retention time: 14.38 minutes; purity: 99.75; MS (mass/charge): 381.07 (MN). 7.341176 M2,MaA-bis(3-amino-5- Analogous to the preparation of M2,M4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4» methoxycarbonylphenyl)-2,4-pyrimidinediamine, M2,M4 -bis(3-amino-5-methoxycarbonylphenyl)-72,4-pyrimidinediamine (2950132) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloropyrimidine and 3-amino-

C-Methoxycarbonylaniline LC/MS: retention time: 15.25 minutes; purity: 93.65; MS (mass/charge): 409.02 (MNK). 19 7.3.177 2,M4-bis(3-amino-5- Analogous to the preparation of M2,44-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-trifluoromethylphenyl)-2,4-pyrimidinediamine, IM2,M4-bis(3-amino-5-trifluoromethylphenyl)-2,4-pyrimidinediamine pyrimidinediamine (K950143) is obtained as a result of the reaction of 2,4-dichloropyrimidine and 3-amino-5-trifluoromethylaniline. LC/MS: retention time: 23.23 minutes; profitability: 99.10; MS (mass/charge): 428.95 (MN.Yu). 7.3.178 M2.M4-bis(3-amino-5-chlorophenyl)-72,4- Similar to the preparation of M2,M4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine (K950133 ) of pyrimidinediamine, M2,M4-bis(3-amino-5-chlorophenyl)-2,4-pyrimidineliamine is obtained as a result of the reaction of 2,4-dichloropyrimidine and 3-amino-5-chloroaniline.

LC/MS: retention time: 19.45 minutes; purity: 10095; MS and (mass/mass): 360.93 (MNN. 7.3.179 MO Ma-bis(3-amino-4-(M-phenylamino)- Analogous to the preparation of M2,Ich4-bis(3-amino-4-nitrophenyl) -5-fluoro-2,4- phenyl|-5-fluoro-2,4-pyrimidinediamine pyrimidinediamine, M2Mm4-bis|3-amino-4-(M-phenylamino)-phenyl|-5-fluoro-2,4- (K950125) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and

Z-amino-4-(M-phenylamino)-aniline. LC/MS: retention time: 23.67 minutes; purity: 10035; MS (mass/charge): 476.36 (MN). at 74180 2.4. bis|Z-amino-4OM.-phenylamino)- Similar to the preparation of M2,M4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-phenyl|-2,4-pyrimidinediamine (K950123) pyrimidinediamine, M2, ІМ4-bis| 3-amino-4-(M-phenylamino)-phenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloropyrimidine and 3-amino-4-(M-phenylamino)-aniline. LC/MS: retention time: 23.77 minutes; purity: 77.895; MS (mass/charge): 475.04 (MNK). (Se) 7zavVi M2,MA-bis(5-amino-2-methylphenyl)-5- Similar to the preparation of M2,M4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-fluoro-2, 4-pyrimidinediamine (KO50157) pyrimidinediamine, M2,4-bis(5-amino-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (22) is obtained by the reaction of 2,4-dichloro-5-fluoropyrimidine and 5 -amino-2- methidaniline. LC/MS: retention time: 10.61 minutes; purity: 83.45; MS che (mass/mass): 339.13 (МН... 7.3.182 M2,M4-bis(5-amino-2-fluorophenyl)-5- Analogously to the preparation of M2,M4-bis(Z-amino-d- nitrophenyl)-5-fluoro-2,4-sem fluoro-2,4-pyrimidinediamine (K950158) pyrimidinediamine, M2,M4-bis(5-amino-2-fluorophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained in resulting from the reaction of 2,4-dichloro-5-fluoropyrimidine and 5-amino-2-cofluoroaniline. LC/MS: retention time: 11.48 minutes; purity: 95.65; MS (mass/charge): 347.04 ( 7.3.183 M2,MA-bis(3-amino-4-fluorophenyl)-5- Similar to the preparation of M2,M4-bis(3-amino-4-nitrophenyl)-5-fluoro-2,4-fluoro- 2,4-pyrimidinediamine (K950159) of pyrimidinediamine, M2.M4-bis(3-amino-4-fluorophenyl)-5-fluoro-7,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimiline and З- amino-4-" fluoroaniline. LC/MS: retention time: 18.74 minutes; purity: 95.60; MS mass/per; : 347.29 (MNK). and ( row). and ) from 7.3.184 M2 /M4-bis(o-methyl-z-nitrophenyl)-5-2,4-dichloro-5-fluoropyrimidine (33 mg, 0.2 mmol) is dissolved in a mixture of MeOH (1 ml) with fluoro-2,4-pyrimidinediamine (K9 50146) and H2O (0.4 ml). 2-methyl-5-nitroaniline (122 mg, 0.8 mmol) was added to the mixture and heated in a reflux flask for 2 days (oil bath temperature: 700 °C). After that, the mixture was cooled to 220 °C, concentrated dry state under reduced pressure and subjected to column chromatography on silica gel (SNCI3-acetone, 9:1) in order to obtain M2,M4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (0M50-y6-SOZOB): PO 8.31 (8, 1H, 252.3 Hz), 8.20 (0, 1H, 1- 2.3 Gy), 8.06 (0, IN, 2-2 3.5 Р sh), 7.91 (49, IN, 1» 2.3:8.2 Gy), 7.55 (ai, 1H, 4-2.9; 8.8 Go), 7.41 (t, IN), 7.28 (4, 1H, 7 8.2 Go), 2.28 so (5, ZNU, 2.24 (5, ZN); RH/MS purity: 87495; MS (mass/charge): 399.20 (M, 100) from 7.3.185 MMA bis(2-fluoro-5-nitrophenyl)-5-fluoro- | Similar to the preparation of M2,Ma4-bis(2-methyl-5- nitrophenyl)-5-fluoro-2,4-2,4-pyrimidinediamine (K950147) of pyrimidinediamine, YCh2,44-bis(2-fluoro-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4 -dichloro-5-fluoropyrimidine and 2-fluoro-5-nitroaniline. LC/MS: retention time: 31.07 minutes; purity: 93.65; MS (Ce) 42) ko 60 b5 write PPP ON SESSION 7.3. 186 M2,M4-bis(4-fluoro-3-nitrophenyl)-5-fluoro- | Analogous to the preparation of 142, M44-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4- 2,4-pyrimidinediamine (K950148) pyrimidinediamine, M2,M4-bis(4-fluoro-3-nitrophenyl)- 5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-lichloro-5-fluoropyrimidine and 4-fluoro-3-nitroaniline. LC/MS: retention time: 27.17 minutes; purity: 94.390; MS (mass/charge): 406.96 (MN). 7.3.187 M2, Ma-bid(4-methyl-3-nitrophenia)-5- Similar to preparation 2, M4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4- fluoro-2,4 -pyrimidinediamine (К950144) pyrimidinediamine, M2/M4-bis(4-methyl-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-methid-3 » nitroaniline. LC/MS: retention time: 27.40 minutes; purity: 96.690; MS (mass/charge: 399.00 (MENU). 7-3.188 M2,Ma-bis(4-chloro-3-nitrophenyl)-5-fluoro- | Similar to the preparation of M2,M4-bis(2-methyl-5- nitrophenyl)-5-fluoro-2,4- - 2,4-pyrimidinediamine (KUZO149) of pyrimidinediamine, M2,M4-bis(4-chloro-3-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4- of dichloro-5-fluoropyrimidine and 4-chloro-3-nitroaniline. LC/MS: retention time: 35.63 minutes; purity: 98.995; MS (mass/charge): 439.09 (MN). 7.3.189 2, M4 -bis(2-hydroxyethylamino-5-) Similar to the preparation of M2,M4-bis(2-methyl-5-nitropheny)-5-fluoro-2,4-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine|pyrimidinediamine, M2,M4 -bis(2-hydroxyethyleneamino-5-nitrophenyl)-5-fluoro-2,4- (К950150) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 2-hydroxystipenamino-5-nitroaniline. LC/MS: retention time: 17.90 h; purity: 97.895; MS (mass/charge): 489.19 (Mn.U). 7-3.190 M2,M4-Bis(2-methoxy-5-nitrophenyl)-5- Analogously to preparation M2, M4-b16(2-methyl-5-nitrophenyl)-5-fluoro-2,4-fluoro-2, 4-pyrimidinediamine (K950151) pyrimidinediamine, M2,M4-bis(2-methoxy-5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 2-methoxy- 5- Vitrognilin. LC/MS: retention time: 31.46 minutes; purity: 95.995; MS (mass/charge: 431.22 (MNK). 7.3.191 MO Ma-bis(4-fluoro-Z-nitrophenyl)-2,4- Similar to the preparation of M2,M4-bis(2-methyl-5-nitrophenyl) -5-fluoro-2,4-pyrimidinediamine (KU50152) pyrimidinediamine, M2,M4-bis(4-fluoro-3-nitrophenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloropyrimidine and 4-fluoro-Z - nitroglycerin,

LC/MS: retention time: 30.92 minutes; purity: 94.49; MS (mass/charge): 389.31 (MNK). 2.3.192 M2,M4-bis(4-methyl-3-nitrophenyl)-2,4- Analogous to the preparation of M2,M4-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4- pyrkmidikidiamine (KO50153 ) of pyrimidinediamine, M2,M4-bis(4-methyl-3-nitrophenyl)-2,4-pyrimidinediamine are obtained as a result of the reaction of 2,4-lichloropyrimidine and 4-methyl-3-nitroaniline. (Se) 7 F

LC/MS: retention time: 31.22 minutes; purity: 99.695; MS (mass/charge): 381.35 (MNE. che 7.3.1193 M2MmA-bis(4-chloro-3-nitrophenyl)-2,4- Similar to the preparation of M2,M4-bis(2-methyl-5-nitrophenyl) -5-fluoro-2,4-pyrimidinediamine (KO50154) of pyrimidinediamine, М2,М4-bis(4-chloro-3-nitrophenyl)-2,4-pyrimidinediamine sc is obtained as a result of the reaction of 2,4-dichloropyrimidine and 4-chloro- 3-nitroaniline,

MOVEMENT/MS: duration of detention: 37.24 minutes; purity: 99.15; MS (mass/charge): 421.30 (MNE. (ee) 7.3.194 M2,M4-bis(2-hydroxy-5-nitrophenyl)-2,4- | Similar to the preparation of M2,M4-bis(2-methyl -5-nitrophenyl)-5-fluoro-2,4-pyrimidinediamine (K950155) tyrimidinediamine, M2.M4-bis(2-hydroxy-5-nitrophenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloropyrimidine and 2-hydroxy-5-nitroaniline. LC/MS: retention time: 23.26 minutes; purity: 10090; MS (mass/charge): 385.33 (MN). " 7.3.195 M2, MA bis(2-hydroxyethyleneamino -5- Similar to the preparation of M2,44-bis(2-methyl-5-nitrophenyl)-5-fluoro-2,4-nitrophenyl)-2,4-pyrimidinediamine pyrimidinediamine, M72,1х4-bis(2-tihydroxyacetylenamino-5- nitrophenyl)-2,4- - c (8950156) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloropyrimidine and 2-thydroxyethyleneamino-5-nitroaniline. LC/MS: retention time: 17.87 minutes; n z» purity: 97, 29; MS (mass/charge): 470.99 (MH). " 7.3196 M2,M4-bis3-(M-isopropyne)aminophenyl- | M2,M4-bis|Z4(M-isopropyl)aminophenyl-5-fluoro- 2,4-pyrmidinediamine is obtained in z-fluoro-2,4-pyrim ydindiamine (K950166) as a result of the reaction of M2,M4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine, acetone and sodium psnanobohydride. РЧ/МС: duration of retention; 14.07 minutes; purity: 90.395; MS (mass/charge) in: 395.14 (MNK). (ee) 7.3.197 M2,M4-bis(3-M-(2-hydroxy-1- M2,Ma-bis(3-M-(2-hydroxy-1-methylethyl)aminophenyl|-5-fluoro-2 ,4-pyrimidinediamine methylethyl)aminophenyl-5-fluoro-7,4- is obtained as a result of the reaction of M2,M4-bis(3-aminophenyl)-5-fluoro-7,4-km pyrimidinediamine (К950171) pyrimidinedismine, 1-hydroxyacetone and sodium cnanoborohilride. LC/MS: retention time: 11.97 minutes; purity: 79.01; MS (mass/charge): 427.12 (Mne. bis(3-tert- M2,Ma-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine butoxycarbonylmethyleneaminophenyl)-5- is obtained as a result of the reaction M2,M4-bis(3-aminophenyl)-5- fluoro-2,4-(Ce) fluoro-2,4-pyrimidinediamine (K950177) pyrimidinediamine and tert-butyl bromoacetate.. LC/MS: retention time: 29.34 min; purity: 97.29; MS (mass/charge) : 427.07 (МН). 0 7.3.199 4-(3-aminophenia)-M2-(3-tert- Similar to the preparation of M2,M4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-butoxycarbonylmethyleneaminophenia)-5- | 5- fluoro-2,4-pyrimidinediamine, M2,M4-bis(3-amine ophenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (K950178) pyrimidinesamine and tert-butyloroacetate enter into a compatible reaction with the formation of IM4-(3-aminophenyl)-M2-(3-tert-butoxycarbonylmethyleneaminophenyl)- 5-ko 60 b5 of fluoro-2,4-pyrimidinediamine. LC/MS: retention time: 18.33 minutes; purity: 94.505; MS (mass/charge): 369.09 (MN KU. 7.3.200 M2-43-aminophenyl)- Ma-(3-tert- Analogously to the preparation of M2,144-bis(3-tert-butoxycarbonylmethyleneaminophenyl)- butoxycarbonylmethyleneaminophenyl)- 5- | 5-fluoro-2,4-pyrimidinediamine, M2-(3-aminophenyl)-M4-(3-tert-fluoro-2,4-pyrimidineliamine (K950179) butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result reactions of M2,M4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and tert-butylbromoacetate, LC/MS: retention time: 18.82 minutes; purity: 85.89;

MC (mass/mass): 369.11 (MN). 7.3.201 Ma. Mi-bi3- Similar to the preparation of M2,M4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-ethoxycarbonylmethyleneaminophenyl)-5-5-fluoro-2,4-pyrimidinediamine, M2,44-bis(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-2 ,4-pyrimidinediamine "K950184) fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M2,144-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and ethyl bromoacetate. LC/MS: retention time: 23.41 minutes; purity: 96.395; MS (mass/charge): 483.08 (МН. 7.3.202 М2,МаА-bis(3- Analogous to the preparation of М2,М4-bib(3-tert-butoxycarbonylmethyleneaminophenyl)- ethoxycarbonylmethyleneaminophenyl)-иМ2- | 5-fluoro-2 . ) of 12,M4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and ethyl bromoacetate.

LC/MS: retention time: 25.65 minutes; purity: 92.59; MC (mass/charge): 569.08 (MN). 7.3.203 M243"aminophenyl)-M443" Similar to the preparation of M2,M4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-hydroxyacetylenaminophenyl)-5-fluoro-2,4-5-fluoro-2,4-pyrimidinediamine, an inseparable mixture of M2- (3-aminophenyl)-M4-(3-pyrimidinediamine and M4A-(3-aminophenyl)-hydroxyethyleneaminophenyl)-3-fluoro-2,4-pyrimidinediamine and MA-(3-aminophenyl)-M2-

М2-(3-hydroxyacetylenaminophenyl)-5-(3-tihydroxyacetylenaminophenyl)-5-fluoro-2,4-pyrimelindiamine is obtained in fluoro-2,4-pyrimidinediamine (K950180) as a result of the reaction М7,Ма4-bis(3-aminophenyl)- 5-fluoro-2,4-pyrimidinediamine and 1-bromo-2-hydroxyethane. LC/MS: retention time: 9.84 minutes; purity: 89.595; MS (mass/charge): 355.10 (MN). 7.3.204 M2,M4-bis(3-hydroxyethylaminophenyl)- | Similarly to the preparation of M2,M4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)" 5-fluoro-2,4-pyrimidinediamine (H950181) 5-fluoro-2,4-pyrimidinediamine, M2,M4-bis(3-hydroxyacetylenaminophenyl)-5- fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M2,Ma4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and I-bromo-2-hydroxystane. LC/MS: retention time: 11.46 minutes; purity: 83.395; MS (mass/charge): 399.12 (MIN-K). 7.3.205. Ma-bisi 3-(M-benzyloxyethyleneamino)phenyl|-5-o 2,4-pyrimidinediamine (К950174) fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of ХМ2, Мм4-bis(3-aminophenyl)-5-fluoro-2, 4-pyrimidinediamine and 1-benzyloxy-2-bromoethane. LC/MS: retention time: 32.92 minutes; MS (mass/charge): 579.17 (CHANGE). 7.3.206 7M2-(3-aminophenyl)-M4 -13-(M- Analogously to the preparation of M2,M4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-benzyloxyethyleneamino)phenyl|-5-fluoro-5-fluoro-2,4-pyrimidinediamine, M2-(3-aminophenyl)-yM4- 1340М- (Те) 2,4-pyrimidinediamine (K950175) benzyloxyethyleneamino)phenyl|-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction M2,M4-bio(3-aminophenyl)-5-fluoro-2,4- pyrimidinediamine and 1-benzyloxy-2-bromoethane. LC/MS: retention time: 23.79 minutes; MS b" (mass/charge) in: 44511 (MNK). 7.3.207 Ma44(3-aminophenyl)-m2-(3-(0M- Analogously to the preparation of M2,M4-bis(3-tert-butoxycaroniummethyleneaminophenyl)»- h- benzyloxyethyleneamino)phenyl|-5-fluoro-5-fluoro-2 . 3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and 1-benzyloxy-2-bromoethane LC/MS: retention time: 23.64 minutes; MS o (mass/charge): 445.13 (MH). 7.3.208 Ma4(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | To a solution of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidivamine (0.028 g, (3-tihydroxyphenyl )-2,4-pyrimidinediamine 0.1 mmol) in MeOH:HO (1.8: 0.2 mL) add 3-hydroxyaniline (0.033 g, 0.3 (K926210) mmol) and heat the mixture in a sealed tube at at a temperature of 1000 for 24 hours. The reaction mixture is dissolved in water (10 ml), acidified with M NOSI solution (pH 22), saturated and filtered solid fraction formed in order to obtain the necessary product ukta -M4-(3,4-ethylenedioxyphenyl)-5-fluoro-IM2-(3-hydroxyphenyl))-2,4-pyrimidinediamine (K926210). - c Purification can be carried out by filtration through a silica gel pad using a 1-595 solution of MeOH in CH2CI2, or by t crystallization using an appropriate solvent system. 1H YAM (SOSIZ and t -SOozOru: 0 7.76 (655, 18), 7.30 (8, 1H,2- 2.4 Hz), 7.10 (t, 1H), 7.03 (6 IN, 75 : 8.1

Gy), 6.89 (44, 2H, 7- 2.4 and 9 Hz), 6.78 (y, 1H, 1- 8.7 Hn), 6.42 (ad, 1H, 1-24 and 9

Gy), 4.22 (t, 4H); 19E NMR (SOSIZ SOZO0u: -47196; LC/MS: retention time: 19.55 minutes; purity: 9590; MS (mass/charge): 355 (MNK).

Note: if the substrate has the properties of ethyl, butyl, benzyl and similar ethers, and the reaction takes place in methanol, which plays the role of a solvent, cross-esterification is observed, leading to the formation of methyl

Kkz ether. Sho 7.3.209 M2-(33,4-ethylenedioxyphenyl)-5-fluoro-MA- Similar to the preparation of Ma-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- shk 3-(hydroxymethyl)phenyl|- 2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(3,4-styrenedioxyphenyl)-5-fluoro-M4-(3-(Ce) 42) ko 60 b5 pyrimidinediamine (KU25758) (hydroxymethyl)phenyl-2 ,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-Ma-|3-(hydroxymethyd)phenyl|-4-pyrimylamine and 3,4-ethylenedioxyniline. 1H NMR (SOSIS): PI 7.92 (6, IN, 3-3.0 Hz), 7.78 (B, 1NU, 7.41-7.31 (t, Z), 7.12 (4 ,

IN, In 7.2 Gy), 6.94 (5, 1H), 6.81-6.75 (t, ZNI), 4.68 (5, 2H), 4.25 (in, 4NU; I9E YAM (SOSIZ): -47438; LC/MS: retention time: 17.73 minutes; purity: 100 92;

MS (mass/charge): 369 (MNK). 7.3.210 142-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-х2-(3-(4-(hydroxymethyl)phenyl|-2 ,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(3,4-styrenedioxyphenyl)-5-fluoro-M2-14-pyrimidinediamine (К925760) (hydroxymethyl)phenyl|-2,4-pyrimidinediamine is obtained as a result of reaction 2 -chloro-5-fluoro-M4-|4-(hydroxymethyl)phenyl|-4-pyrimidinamine and 3,4-ethylenedioxyaniline.

IN NMR (SSZ): 11 7.92 (65, IN), 7.62 (0, 2H, 1- 8.7 H p), 7.36 (9, 2H, 1- 8.7 Hz), 7198 , 1H, 1-2 2.1), 6.87 (64, 1H, 1- 2.7 and 8.7 Hz); 6.79 (8, EN, 128.7 Go), 4.68 (v, 2NI), 4.28-4.23 (t, 4H); 19E NMR (SOSIS): -4.7466, LC/MS: retention time: 17.86 minutes; purity: 93 95; MC (mass/mass): 369 (MIN. 7.3.211 12-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3 - (d-hydroxy-2-phenylethyl)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(3,4-ethylenedioxyphenyl)-5-fluoro-yM2-(2-pyrimidinediamine (K925765) hydroxy-2 -phenylethyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-4(2-hydroxy-2-phenylethyl)-4-pyrimidinamine and 3,4-styrenedioxyaniline. 1H NMR (SRS) : 0 7.79 (5, 1H), 7.48 (t, 5H), 6.89-6.71 (ta, ZNU, 5.41-5.38, 4.97 (a9, 1, I 3 .6 and 7.5 Hz), 4.28-4.22 (t, 4H), 3.88 (a(d, 1H, 7 4.2; 7.2, and 14.1), 3.64 - 3.55 (t, IN; 19E NMR (SOSIZ): "47910; LC/MS: retention time: 20.47 minutes; purity: 88 5; MS (mass/charge): 383 (MNK). 7.3.212 142-(3,4-ethylenedioxyphenyl)-5-fluoro-Ма4- Similar to the preparation of M4-(3,4-ethylenedioxyphenia)-5-fluoro-М2-(3-

HO) hydroxy-(15)-methyl-2-phenylethyl)- | hydroxyphenyl)-2,4-pyrimidinediamine, M2-(3,4-ethylenedioxyphenyl)-5-fluoro-MA-((28)-2,4-chnrymidindisimine "(K925766) hydroxy-(15)-methyl-2-phenylethyl )-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-MA-((2K)-hydroxy-(15)-methyl-2-phenylethyl)-4-pyrimidinediamine and 3,4-ethylenedioxyaniline. IN NMR (SOSTZ): C 7.80 (65, 1), 7.71 (B5, 1NU, 7.36-7.23 (t. 5H), 6.91 (ai, 1H, 3- 3.0 and 9.0 Hn), 6.80 (4, IN, 21-90 Gy), 5.17 (8, 18, 1-8, g), 5.01 (9, 1, 72 3.0 Go) . ,43 minutes; purity: 99 90; MS (mass/charge): 397 (MH). 7.3.213 Ma-cyclohexyl-im2-(3,4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluorine -M2-(3-ethylenedioxyphenyl)-5-fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M4-cyclohexyl-M2-(3,4-ethylenedioxyphenyl)-pyrimidinediamine (K925794) 5-fluoro-2, 4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-si and cyclohexyl-5-fluoro-4-pyrimidinamine and 3,4-styrenedioxyaniline. IN NMR. 21 7.62 (40.1H, 3-4.2 Hz), 7.314, 1H, 1-21 Gy), 6.85 (4, IN, 7- 2.4 and « 8.7 Hz), 6, 68 (4, 1H,3-8.7 Hz), 4.23-4.16 (t, YAN), 3.99-3.89 (t, 18), 2.03 (49, 2H, 3- 2.1 and 12.3 Hz), 1.80 (а, 2Н, 2- 3.0 and 13.5 Hz), 1.72-1.65 (t, 18, 1.49-1.20 ( t, 5H); 192 NMR (SOZOB): -48332; LC/MS: retention time: 24.54 minutes; cleanliness: - p. 95 5; MS (mass/charge): 345 (MNK). 7.3.214 Ma-(4-carboxycyclohexyl)-42-(3,4- Analogously to the description M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3- x ethylenedioxyphenyl)-5-fluoro-2, 4-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(4-carboxycyclohexyl)-M2-(3,4-" pyrimidinediamine (K925795) ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinedismine is obtained as a result of the reaction

M4-(4-carboxycyclohexyl)-2-chloro-5-fluoro-4-pyrimidinamine and 3,4-ethylenedioxyaniline. IN NMR (SOZOB): 2 7.62 (a, IN, 22:4.2 Hu, 7.314, IN, 2- 2,A gy), 6.84 (40, 1H, 2: 2.4 and 8, 7 Hz), 6.70 (y, IN, 32: 8.7 Hz), 4.23-4.18 (t, 48), o 3.99-4.08 (tp, 1H), 2.59 (6, IN, 7- 3.9 Gy), 2.16-2.09 (t, 2H), 1.91. 1.84 (t, 2H), 1.78-1.57 (t, 4NU; 192 NMR (СО300): -48152; LC/MS: retention time: 19.31 minutes; purity: 96 95; MS (mass /zaryal): 389 (MENU). ki 7.3.215 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- (3-hydroxyphenyl)-2,4-pyrimidinediamine hydroxyphenia)-2,4-pyrimidinediamine, M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- - (K925796) hydroxyphenyl)-2,4- pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-

Ma-(3-tihydroxyphenyl)-4-pyrimidinamine and 3,4-ethylenedioxyaniline. IN NMR (se) (0РМ50-46): 1 9.30 (5, 1), 9.12 (65, IN), 8.91 (B5, IN), 8.02 (y, IN, /- 3.3 Gy), 7.35-7.30 (t, IN), 7.24-7.21 (t, NEO, 7.120, 1H, 1- 1.8 Gy), 7.09-7.04 (t, 2), 6.67 (d,

Pr IN, 1- 9.0), 6.46 (ai, IN, 3- 1.8 and 8.4 Hz), 4.18-4.12 (t, 4H); CE NMR (OM5O-46): -46594; LC/MS: retention time: 18.43 minutes; purity: 97 90; MS (mass/charge): 355 (MNY). 7.3.216 М2-алип-м4-(3,4-ethylenedioxyphenyl)-5- Analogously to М4-(3,4-styrenedioxyphenyl)-5-fluoro-М2-(3-fluoro-2,4-pyrimidinediamine) (K925823) hydroxyphenyl)-2,4-pyrimidinediamine, M2-allyl-M4-4(3,4-ethylenedioxyphenyl)-5-fluoro-2,A-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl) -5-fluoro-4-pyrimidinamine and zylylamine. IN NMR (SOZOB): Gi

HF) 7.71 (B5, 1), 7.37 (4, 18, 252.4 Hz), 7.07 (4d, 1H, 1- 2.4 and 8.7 Hz), 6.75 (0 , IN, 1- 8.7 Gy), 5.98-5.85 (t, 1H), 5.19 (d9, 1H, /e: 1.8 and 16.8 Hz), 5.06 (da . / MS: retention time: 19.36 minutes; purity: 95 25; MS (mass/charge): 303 (MH). in 7.3.217 ma-(3,4-styphenedioxyphenyl)-іCh244-і Analogous to the preparation of a-( 3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-ethylphenyl)-5-fluoro-2,4-pyrimidinediamine | hydroxyphenyl)-2,4-pyrimidinediamine, IM4-(3,4-ethylenedioxyphenia)-M2- (4-(К926237) ethylphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-

M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4-stilaniline. IN NMR b5

(SOSIZ); SI 7.87 (65.18), 7.42 (8, UN, 1-5 8.7 Gy), 7.26 (4, 18, 72 3.0 and), 7.13-7.08 ( t, ZN), 6.95 (44, 1H,, 72.4 and 8.7 Hz), 6.624, 1H, 7 9.0 Gy), 6.60 (B5, IN), 4.23 (5, 4H), 2.59 (d, 2H, 1-7.5 Go), 1.204, ЗН, 1- 7.5 Gy); 19E NMR (SOSIZ): -47549;

РЧ/МС: duration of retention; 2531 minutes; purity: 99 90; MC (mass/charge): 367 (MN). 2 7.3.218 Ma-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(2-(methoxycarbonyl)benzofuran-5-1l1-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-ethylenedioxyphenyl )-5-fluoro-M2-12-2,4-pyrimidinedismin (K925690) (methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5 -fluoro-4-pyrimidinamine and 2-methoxycarbonyl-5-aminobenzofuran. NN NMR (0M50-46); GI 9.68 (65, 1H), 8.13- 8.10 (t, 2H), 7.63- 7.54 (t, ZN), 7.27 (5, IN), 7.10 (4, IN, 2-87 Hn), 6.80 (j, IN, I- 8.1 Hz), 4.21 ( 5, 4H)), 3.88 (5, ZNU); LC/MS: retention time: 23.22 minutes; 70 purity: 95 96; MC (mass/charge): 437 (MN). 7.3.219 5-fluoro-M2-(2- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl|- 5-fluoro-42-(3- methoxycarbonylbenzofuran-5-yl)-M4-(4- | hydroxyphenyl)-2 ,4-pyrimidinedismicum, 5-fluoro-M2-(2-methoxycarbonylbenzofuran-5-isopropoxyphenyl)-2,4-pyrimidinediamine | yl)-Ma-(4-isopropoxyphenial)-2,4-pyrimidinediamine is obtained as a result of the reaction (8926704) 2-chloro-5-fluoro-m4-H4-(isopropoxy)phenyl|-4-virimidinamine and 2-methoxycarbonyl-5-aminobenzofuran.IN NMR (SOSIS): 0 8.044, 1H, 35 1.8 Ho), 7, 49-7.41 (t, 4nu, 7.35 (44, IN, 1 24 and 8.7 Hz), 7.14 (Bo, 1H)), 6.90 (4, 2H, 1» 9.3 Hz), 6.70 (65, 1H), 4.55 (2a, 1H, 1 5.7 Hz), 3.98 (5, Z), 1.37 (d, 5H, 12 5.7 Gu, LC/MS: retention time: 25.52 minutes; purity: 98 90; MS (mass/charge): 437 (MH). 7.3.220 5-fluoro-M4-(3-hydroxyphenyl)- M2-I442- Similar to preparation M443,4-Sethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyethyl)oxyphenyl|-2,4-hydroxyphenyl)-2,4-pyrimylidenediamine, 5-fluoro-M4-(3-hydroxyphenyl)-M2-(4 -(2- pyrimidinediamine (4926376) hydroxyethyl oxyphenyl-2,4- pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-m4-(3-hydroxyphenia)|-4-pyrimidinamine and 4-(2-hydroxytiloxy aniline). IN NMR (020; r18.40 (a, 18 34-54 Hz), 7.57 (t, 6H), 7.12 (t, 2H), 6.90 (t, 2H), 4.40 ( t, 4H)) 2.9 (5, ЗН); LC/MS: retention time: 13.61 minutes; purity: 97 g; MS (mass/charge): 357 (MNK). 7.3.221 m2-(4-(2-MM- Analogously to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-dimethylamino)stoxyphenyl|-5-fluoro-M4- hydroxyphenyl)-2, 4-pyrimidinediamine, M2-14-(2-M,M-dimethylamino)ethoxyphenyl|-3-(3-hydroxyphenyl)-2,4-pyrimidinediamine fluoro-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained in as a result of the reaction of 2-(K909236) chloro-5-fluoro-M4-(3-hydroxyphenyl)|-4-pyrimidinamine and 4-(2-M,M. dimethylamino)sthoxyaniline. IN NMR(CO3O0): 77.80 (4 , 1H 1-4 Hz), 7.47 (44, sem

IN. 1-68 Hz, 2.7 Hz), 7.44 (t, 1 NU, 7.05 (t, 1NU, 6.85 (t, 1), 6.78 (t, 28), 4.16 (t, 2H), 3.03 (to, 2H), 2.55 (5, 6H); LC/MS: retention time: 12.74 minutes; Ho) 52100020 ren vm aslovyuuzvmnia; 7.3.222 M2-(1,4- benzoxazin-3-one-b-1l)-5-fluoro- Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-ma-(3-hydroxyphenyl)-2,4-hydroxyphenyl) -2,4-pyrimidinedismin, M2-(1,4-benzoxazin-3-one-b-yl)-5-fluoro-M44 pyrimidinediamine (K909238) 3-hydroxyphenyl)-2,4-pyrimidineliamine is obtained as a result of the reaction of 2- chloro-5-(Te fluoro-Ma4-(3-hydroxyphenyl)|-4-pyrimidinamine and compounds 6-amino-1,4-benzoxazine-

Z-he IN NMR (РМ5О-46): 218.18 (4, IN 1-4 Go), 7.17 (t, ZN), 7.09 (t IN ), 7.06 (t, IN), 6.58 (t, 1H) 4.52 (8, ЗН); LC/MS: retention time: 17.18 minutes; (o) purity: 99 95; MS (mass/charge): 368 (MNK). 7.3.2723 M2-(1,4-benzoxazin-b-yl)-5-fluoro-Ma43- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-h-hydroxyphenyl)-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, M2-(1,4-benzoxazine- 6-yl)-5-fluoro-M4-4(3- (К909241) hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-

M44(3-hydroxyphenyl)|pyrimidinamine and b6-amino-1,4-benzoxazine. IN NMR (spZO0) in SPO, 1H, 1-4 Go), 7.15 (t, ZN), 6.68 (t, 2H), 6.52 (t, 2H), 6.52 (t, so

INU, 4.18 (t, 2H), 3.37 (t, 2H); LC/MS: retention time: 17.42 minutes; purity: 9590; MC (mass/charge): 354 (MN). 7.3.224 M4-(1,4-benzoxazin-b-yl)-M2-I(3- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- ethoxycarbonylmethyleneoxyphenia |-5- hydroxyphenyl )-2,4-pyrimidinediamine, M4-(1,4-benzoxazin-b-1l)-M2-(3-fluoro-2,4-pyrimidinediamine (5909242) ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine are obtained as a result of the reaction of М4-4(1,4-benzoxazin-b-yl)-М2-chloro-5-fluoro-4-pyrimidinamine and 3-ethoxycarbonylmethyleneoxyaniline. IN NMR (СО3О2): 128.2 (d, IN, 2 -4 Go), 7.15 (t, 4H), 6.84 (t, 281), 6.62 (t, IN), 2.65 (5, 2H)), 4.15 (t, 4NI) , 3.28 (t, 2H), 1.19 8 (and ZN. 157 Gy); LC/MS: retention time: 22.6 minutes; purity: 9495; MS s (mass/charge); 439 (MNK). p z» 7.3.225 M2-(1,4.benzoxazin-b-yl)-z-fluoro-Ma-(3- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3 - p hydroxyphenia)-2,4-pyrimidinediamine tidproxyphenyl)-2,4-pyrimidinediamine, M4-(1,4-benzoxazin-b-yl)-5-fluoro-M2-(3-(K909243) hydroxyphenyl)-2, 4-pyrimidinediamine is obtained as a result of the reaction of ХМ4-(1,4-benzoxazin-b-yl)-М2-chloro-3-fluoro-4-pyrmidinamine and 3-aminophenol, IN NMR (0М50-46): 127.83 (0 , 1H, 1-4 Gy), 7.18 (t, ZNU, 6.68 (iv, 2NI), 6.45 (t, 2H), 6.52 (t, 1H), 4.22 (t, 2H)), 3.31 (t, 2H); РХ/MS: retention time: 17.24; purity: (ohm) 9695, MS (mass/charge): 354 (MN). 7.3.226 МА41,4-benzoxazin-b-yl)»М2-(3,5- Analogous to the preparation of МА4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-(3-ko dimethoxyphenyl)-5-fluoro- 2,4- hydroxyphenyl)-2,4-pyrimidinediamine, M4-(1,4-benzoxazin-6-yl)-142-(3,55 pyrimidinedismin (K909245) dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M4- shk (i.4-benzoxazin-b-yl)-Mo-chloro-5-fluoro-4-pyrimidinamine and 3,5-dimesthoxyaniline.

IN NMR (0M5O0-46): (3 8.12 (0, 1H, 1-4 Hz), 6.80 (t, 4H), 6.60 (t, 1), 6.05 (t, ( Se) 42) ko 60 b5 pn TNU, 4.02 (t, 28), 3.65 (5, OH), 3.31 (t, 2H); LC/MS: retention time: 22.38 minutes; purity : 99 92; MS (mass/charge): 398 (MIN--). 7.3.727 Ma 4-benzoxazin-6b-yl)-M2-(3-tert- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)- 5-fluoro-M2-(3-butylphenyl)-5-fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M4A-(1,4-benzoxazin-b-yl)-M2-(3-tert- pyrimidinediamine (К909246) butylphenyl)-5-fluoro-2,4-pyrimidinlismine is obtained as a result of the reaction of М4-(1,4-benzoxazin-b-yl)-М2-chloro-5-fluoro-4-pyrimidinamine and З-tert- butylaniline. IN

NMR (0M50-a6u g1 8.0, 1H, Te 4 Hz, 7.5 (t, 1NU, 7.4 (t, 1NU, 7.18 (t, 18), 7.02 (po, IN), 6.80 (t, 28), 6.60 (t, 1H), 4.02 (ho, 2H), 3.31 (t, 2H), 1.2 (v, 9H); LC/MS: duration retention: 26.64 minutes; purity: 99 95; MS (mass/charge): 508 (MNK). 7.3.228 M441,4-benzoxazin-6-yl)-5-fluoro-M2-(4- 1 Analogous to preparation M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(2-hydroxystyl)oxyphenyl)-2,4-tihydroxyphenyl)-2,4-pyrimidinediamine, M4411,4-benzoxazin-b-yl) -3-fluoro-M2-(14-(2-pyrimidinediamine (К909248) tihydroxyethyl)oxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction M4-(1,4-benzoxazin-6-yl)-Х2-chloro-5 -fluoro-4-pyrimidinamine and 4-42-hydroxyethyl)oxyaniline. IN NMR (0M50-4y6): GP 7.98 (y, 18, 35:4 Su, 7.52 (t,

IN), 7.4 (t, ZE), 6.90 (t, 281), 6.68 (t, IN), 4.56 (5, 2H)), 4.02 (t, 2H), 3 .75 (t, 2H), 3.31 (t, 4H); LC/MS: retention time: 26.67 waves; purity: 93 95;

Me(t/e): 399 (MN). 7.3.229 M2-(2,3-dihydrobenzofuran-5-yl)-5-fluoro- | Similarly to the preparation of m4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-

M4-(3-tihydroxyphenyl)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(2,3-dihydrobenzofuran-5-1l)-5-fluoro-Ma-pyrimidinediamine (2909250) (3-tihydroxyphenyl) -2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)|-4-pyrimidinamine and 5-amino-2,3-dihydrobenzofuran.

INYAMR (0M50-46): O 8.09 (d, 18), 8.00 (t, EN), 7.82 (t, 1H), 7.57 (t, 1H), 7.22 (t, IN), 7.08 (t, IN), 6.99 (t, 11), 6.82 (t, 1H), 6.70 (pa, 1H)), 6.42 (t, 1H), 4 ... benzoxazin-b-yl)-M2-(3-chloro-4- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxy-5-methylphenyl)-5-fluoro-2 . 4-pyrimidinediamine is obtained as a result of the reaction of MA-(1,4-benzoxazin-6-1ya)-M2-chloro-5-fluoro-4-pyrimidinamine and 3-chloro-4-tihydroxy-5-methylanidine. IN NMR (0ОМ5О- 46): GI 7.89 (40, 1H, 7-2 4 Hz), 7.25 (t,

IN), 7.14 (t, 18), 6.50 (t, 2), 6.82 (po, 1), 4.29 (5, 2H), 3.35 (t, 2H), 2, 20 (5, ZNU;

LC/MS: retention time: 17.05 minutes; purity: 99 95; MO(t/e): 402 (MN). 7.3.231 5-fluoro-M2-(2,3-dihydro-2- Analogous to the preparation of M4-(3,4-stiphenedioxyphenyl)-5-fluoro-M2-(3- se (methoxycarbonyl)benzofuran-2-yl). M4- | podroxyphenyl)-2,4-pyrimidinediamine, 5"-fluoro-M2-(2,3-dihydro-7"(4-isopropoxyphenyl)-2,4-(methoxycarbonyl)benzofuran-5-1l)-M4- 4-isopropoxyphenyl)-2,4-pyrimidinediamine Ge) pyrimidinediamine (K926706) is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(4-1isopropoxyphenyl)-4-pyrimidinamine and 5-amino-2,3-dihydro- 2-(methoxycarbonyl)benzofuran. IN NMR (SoSIZ): 0 7.87 (a, 1, 1-30 0), 7.47-7.42 (t, ZNU, 7.12 (da, 18, 2-- 2.4 and 8, 4 Gy), 6.87 (9, 2H, 129.6 Gy), 6.80 (d, IN, 1-- 8.7 Gy), 6.63 (0, 1H, 1: 2.4 Go) , 5.21 (44, 1H, (Ce) 1-63 and 10.5 Hz), 4.53 (29, 1H, 2: 5.7 Hz), 3.90 (5, ZN), 3.52 (44, IN, 15 10.5 and 15.9

Hz), 3.35 (44, 1H, 32 6.3 and 15.9 Hz), 1.34 (4, 6H, 7: 5.7 Hz); 192 NMR (SOSIZ): - 47664; LC/MS: retention time: 23.78 minutes; purity: 95 b; MS (o) (mass/charge): 439 (MNK). 7.3.232 5-fluoro-M44(3-hydroxyphenyl)-M2-|442- Similar to the preparation of 1m4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- -- (M-morpholine)styreneoxy |phenyl )-2,4- hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-M4-(3-hydroxyphenyl)-Mm2-14-12-0M- pyrimidinediamine (KU26699) morpholine) acetylenoxy|phenyl|-2,4- pyrimidinediamine is obtained as a result of the reaction between 2-chloro-M4-(3-tihydroxyphenyl)-5-fluoro-4-pyrimidinamine and 4-(24(M-morpholino)ethyleneoxy|aniline. NR NMR (OM 50-46: Gi 9, 34 (in, 1H), 9.17 (65, 1), (ee) 8.95 (5, 1H), 8.02 (4, IN, 1» 3.3 Gy), 7.53 (4, 2H, 1": 9.0 Gy), 7.28-7.23 (t, 1H), 7.12-7.04 (to, 2H, 6.79 (y, 2H, 27- 9.0 Gy ), 6.47 (489, IN, 4-1.2 and 5.7 Gy), 4.006, 2Н,, 42 6.0

Hz), 3.56 (y, NN, 1-4.5 En), 2.64 (b, 2, 1-60 Hz), 2.44 (0 NN, 1-45 Hz; 196 NMR (OM5O- 4b): -46715; LC/MS: retention time: 12.66 minutes; purity: 95 95;

MC (mass/charge): 426 (MN). "7.3.233 МИ4-(3,4-ethylenedioxyphenyl)-5-fluoro-cha" Similar to the preparation of МИ4-4(3,4-ethylenedioxyphenyl)-5-fluoro-М2-(3- (4-(2-(М- morpholine) styreneoxy (phenyl» hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2-(4-(2- 2-in 2,4-pyrimidinediamine (K926709) (M -morpholino)ethyleneoxy|phenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4-I12-(M-morpholino)ethyleneoxyaniline 1 NMR (SPZO): p 7.804, IN, 31- 3.6 Hz), 7.72 p » (B5, 183, 7.62 (65, 1NU, 7.41 (9, 1, 3- 9, 3 C), 7.24 (0, 1H, 1-5.4 Hyd), 7.05 (44, IN, n Te22.4 and 8.7 Gy), 6.84 (0, 2H, 15 8, 7 Hz), 6.75 (y, 1 12: 9.0 Gy), 4.24 (re, 48), 411 (. 2H,21- 5.4 Hz), 3.74-3.69 (ti, 4H ), 2.50 (, 2, 3 5.4 GHz), 2.62-2.58 (t, 4H); 19E NMR (cSrzOYU)u: -47912; LC/MS: retention time: 15.16 minutes purity: 91 95;

MS (mass/charge): 468 (MY Kk). o 7.3.2734 5-fluoro-M2-(3-hyloxyphenyl)-M4-|4-(2- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- (M-morpholinosethyleneoxyIphenyl- 2,4-hydroxyphenyl)-2,4-tyrimidinediamine, 5-fluoro-M2-(3-hydroxyphenyl)-M4-H4-(2-(M-pyrimidinediamine (KO26710) morpholino)ethyleneoxyphenyl |-2,4-pyrimidinediamine are obtained as a result of the reaction of 2-chloro-5-fluoro-im4-I14-|2-(M-morpholino)stylenoxy|phenyl|-4-pyrmidynamin and 3-aminophenol. IN. NMR (SRZOYUU: 1 7.84 (d, 1H, 1: 4.2 Hz), 7.50 (4, 1H. with- 9.3 Hz), shk 7.094 1H, 1-24 Go), 7.04-6.96 (t, 2H), 6 .93 (4, 2H, 1- 9.3 Gy), 6.40 (where, 18, 1-18 and 7.5 Gy), 4.15 (5, 2H, 7: 5.4 Gy), 3 ... ,16 minutes; purity; 98 95; MS (42) ko 60 b5

ShSH202520 00000000 early 12 (With 7.3.235 M2-(3,4-Stylenedioxyphenyl)-5-fluoro-HyMa- Similar to the preparation of M4-(3,4-Stylenelioxyphenyl)-5-fluoro-M2-(3- (442-( M-morpholino) styleneoxy) phenyl|- hydroxyphenyl)-2,4-pyrimidinediamine, 424(3,4-ethylenedioxyphenyl)-5-fluoro-4-I4-(2- 2,A-pyrimidinediamine (K926711) (M-morpholino )stylenoxy |phenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-14-(2-(M-morpholino)ethylenekei |phenyl|-4-pyrimidinediamine and 3,4-ethylenedioxyaniline. IN YAM? (SO3O): 7 7.80 (0, 1H, 7- 4.2 gy), 7.564, 2H, 1- 8.7 Hz), 7.13 (y, 18, 7-5 2.4 Hz), 6.91 (a, 2H, 15 9.6 Hz), 6.86 (an, - 2.4 and 950 Gy), 6.67 (d, 1H, 7- 9.0 Gy), 4 ,23-4.18 (t, 4NI), 4.14 0, ZN, 1- 5.4 Gy), 3.74-3.70 (t, 4NU, 2.82 (5 ZN, 3 5.4 Hz), 2.64-2.59 (t, 4H); 19E NMR (SOSIS): -47914; LC/MS: retention time: 15.97 minutes; purity: 94 0; MS (mass/charge): 468 (MIN). 7.3.236 M4-(3,4-ethylenedioxyphenia)-5-fluoro-M2- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- 70 14-( tetrahydro-"(1H)- pyrrole-1-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-|4-ylsulfonyl)phenyl|-2,4-(tetrahydro-(1H)-pyrrole- 1-ylsulfonyl)phenyl-2,4-pyrimidinediamine is obtained in pyrimidinediamine (K926716) as a result of the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4-(tetrahydro-(1H)- pyrrole (hylesulfonyl)aniline. D IN NMR (0M50-46U: 2 1011 (B5, IN), 9.76 (b, PN), 8.19 (9, 1H, 72: 3.9 Gy), 7.82 ( 4, 2H, 18.7 Sn), 7.62 (0, 2H, 1- 8.7 Gy), 7.279, 1 H, 3-72.4 Hz), 7.08 ai, 1H, 3- 2, 4 and 8.7 Gy), 6.854, 1H, 72 8.7

Hy), 4.23 (5, 4H), 3.10-3.06 (t, 4NI), 1.64-1.58 (t, 4H); LC/MS: retention time: 22.68 minutes; purity: 93 95; MS (mass/charge): 472 (MIC). 73237 2-I3-(4-(2-chloro-6- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- fluorobenzyl)piperazine|ipropyl|-M4-(3,4- | hydroxyphenyl)-2,4-pyrmidineliamine, M2-13-14-(2-chloro-6-ethylenedioxyphenyl)-5-fluoro-2,4-fluorobenzyl)piperazine|propyl|-144-(3,4-ethylenedioxyphenyl) -5-fluoro-2,4-pyrimidinediamine (K926717) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-m443,4.ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3-(4-(2-chloro-b- fluorobenzyl )piperazine|propylamine. IN NMR (SOSIS): 0 7.79 (8, IN, 1- 3.0 Gy), 7.37 (a, 1H, 2: 2.4 Gy), 7.19-7.15 ( t, 2H), 7.00-6.93 (t. 2H), 6.81 (a, 1H, 1-5 8.7 Gu, 6.564, 1H, 2- 2.7 Hz), 5.48 ( b5, IN), 4.27-4.21 (t, 4H), 3.70 (a, 2H, 1-1.8 Gy), 3.36 (a, 2H, 226.3 Hz), 2, 68-2.35 (t, ION), 1.75 (4, 2H, 1: 6.3 Hn); 192 NMR (SOSISU: - 31693, -48483; LC/MS: retention time: 18.20 minutes ; purity: 97 90; MS (mass/charge): 532 (MH). 7.3.238 M2-(4-tert-butylphenyl)-5-fluoro-M2-12,3- | Similar to the preparation of M4-4(3, 4-ethylenedioxyphenyl)-5-fluoro-M2-(3-dihydro-2-(m ethoxycarbonyl)benzofuran- | hydroxyphenyl)-2,4-pyrimidinediamine, IM2-(4-tert-butylphenyl)-5-fluoro-M2-12,3-5-epi-2,4-pyrimidinediamine (926719) dihydro-2-(methoxycarbonyl)benzofuran- 5-11|-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(4-tert-butylphenyl|-2-chloro-5-fluoro-4-pyrimidinamivu and 5-amino-2,3-dihydro-2-( methoxycarbonyl)benzofuran. 1H NMR (0М50-46u С 10.16 o (65, INU, 9.84 (55, IN» 8.16 (4, 18.2 5.4 Hz), 7.56 (4, 2Н , 1- 8.1 Gy), 7.49 (5, 1H), 7.35 (4, 2H, 32: 8.7 Hz), 7.13 (44, IN, 1- 1.8 and 8, 7 Hz), 6.78 (4, 1H, 2: 8.7 Hz), 5.35 (44, 1H, 3- 6.6 and 10.5 Hz), 3.52 (d4, IN, 4- 10.5 and 16.5 Gy), 3.20 (yy, IN, I- 6.6 and 16.5 Hz), 1.27 (5, 94); LC/MS: retention time: 26.52 minutes purity: 96 55;

MC (mass/charge): 437 (MN). (Te) 7.3.239 MAK 5-chloro-1-benzothiophen-3-yl)methyl|- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-

M243,4-ethylenedioxyphenia)-5-fluoro-2,4- | hydroxyphenyl)-2,4-pyrimidinediamine, M4-H(5-chloro-I-benzothiophen-3-yl)methyl|-M2-b pyrimidinediamine (K926721) (3,4-ethalenedioxyphenia)-5-fluoro-2,4 -pyrimidinediamine is obtained as a result of the reaction of 2-chloro-Ma-|((5-chloro-1-bezothiophen-3-yl)methyl|-5-fluoro-4-pyrimidinamine and

Z,4-ethylenedioxyaniline. IN NMR (0М80-6): HI 8.08 (8, 1Н, 3-2 1.8 Hz), 8.024, h- 1Н,1- 8.7 Hz), 7.97 (4, 1Н, 7- 4.8 Gy), 7.63 (5, 1H), 7.42 (da, IN, 1- 1.8 and 953 Hz), 7.07 (в, 1H), 6.85 (49, 1H, 1- 2.4 and 8.7 Go), 6.56 (b, 1H, 1- 8.7 Gy), 4.77 (5, 1H), 4.75 se (5, 1H), 4.14 (5, 4); ЭХ/МС: duration of retention; 25.89 minutes; purity: 97 a;

MS (mass/weight): 444 (MIZ). so 7.3.240 Ma-cZ-chloro-|-benzothiophen-3-yl)methyl|- | Similarly to the preparation of M44(3,4-ethylenedioxyphenyl)-5-fluoro-M24(3-5-fluoro-Mm2-(3-hydroxyphenyl)-2,4.hydroxyphenyl)-2,4-pyrimidinediamine, Ma-G(5 -chloro-1-benzothiophen-3-yl)methyl|-5-pyrimidinediamine (KO26722) fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-1(5-chloro - 1-benzothiophen-3-yl)methyl)-z-fluoro-4-pyrimidinamine and 3-aminophenol. IN NMR (PM80-46): 0 9.47 (f5, 1H), 9.33 (65, IN), 8.78 (05, 1), 8.11 (d4, IN, 1-21 Go), 8.02 (4, 1H, 1-1: 8.7 Sn), 7.98 (0, 1H, 1- 4.5 Gy), 7.69 (5, 18), 7.41 « (aa, IN, 3-18; 8.2 o), 7.07 (х5, EN), 6.92 (4, 1H, 7- 5.4 Gy), 6.82 0, IN, U- V Hu, 6 .34 (4, 1H, 12 6.9 Hz), 4.80 (5, 1H)), 4.78 (in, 1H); РЧ/МС: duration of retention; shsh s 23.32 minutes; purity: 93 25, MS (mass/charge): 402 (MIN). 7.3.241 4-(2-((2-chloro-6-fluorobenzyl|ethyl- ethylenedioxy)-5-fluoro-2,4- hydroxyphenyl)-2,4-pyrimidinedigmine, M4-(2-1(2-chloro-b-fluorobenzylhio|stal|-M2-)» pyrimidinediamine (K926723) (3,4 -styrenedioxy)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-12-((2-chloro-6-fluorobenzylthioethyl-5-fluoro-4-pyrimidinediamine) and 1,4-benzodioxane-b -amine. IN NMR (PMI5O0-46): P 9.09 (B5, 1NI), 7.94 (B5, IN), 7.87 (d,

IN, 1-42 Gy), 7.34-7.30 (t, 2), 7.24-7.18 (t, 28), 7.01 (44, 1H, 7-24 and 8.7 Gy ), 6.68 (y, 1H, ze: 8.7 Hz), 4.11 (5, 4H), 3.83 (4, 7H, 2" 1.2 Hn), 3.63-3.56 (t, 2), 2.74 (6 (ee) 2H,1- 7.5 Gy); PH/MS: trivalent retention: 25.17 minutes; purity: 92 90; MS (mass/charge): 466 (MH), co M2-(2,3-dihydro-1,4-benzodioxin-b- Analogous to the preparation of 2-chloro-im4-4(3,4-ethylenedioxyphenyl)-5-fluoro -M2-(3-ylmethyl)-5-fluoro-imi-(3-hydroxyphenyl)» hydroxyphenyl)-2 4-pyrimidinamine, M2-(2,3-dihydro-1,4-benzodioxin-b-ylmethyl)-3 » -y (Se) 42) ko 60 b5

2,4-pyrimidinediamine (K945168) fluoro-Ma-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-4(3-tihydroxyphenyl)-4-pyrimidinamine and 2, 3-dihydro-1,4- benzodioxin-b-yl-methylamine, 1H NMR (SOSIS) HI 4.24 (in, 4 H), 4.45 (4, 756.0 Gy, 2 NU, 6.55 ( give, 2: 0.9; 2.4 and 8.4 Hz, 1 H), 6.66 (4, I H), 6.84 (t, 4 H), 6.90 (t, ! H), 7LA4 (6 Te 8 Sc, 1 NU, 7.30 (t, 1 NU, 7.86 (0, 12 3.3 Hz, 1 NU; 19E YAM (282 MHz,

SRS) O -170.44; LC/MS: retention time: 18.33 minutes; purity: 96.7595;

MS (mass/charge): 369.03 (MH-SU. 7.3.243 Ma-(244(2-chloro-6-fluorobenzyl)thio|ethcl|) Similar to the preparation of 144-(3,4-ethylenedioxyphenyl)-5- fluoro-M2-(3-5-fluoro-m2-(3-hydroxyphenyl)-2,4- hydroxyphenyl)-2,4-pyrimidinediamine, M4-H2-((2-chloro-b-fluorobenzyl|styl|-5 - pyrimidinediamine (KU26724) fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-Mma-12-Х2-chloro-6-fluorobenzylthioethyl-5-fluoro-4-pyrimidinamine and 3-aminophenol. 1H NAM (methyl sulfoxide -d6b): 0 9.76 (B5, 1H), 9.42 (B5, IN), 8.70 (B5, IN), 8.02 (4, IN, 3 -5, Hn), 7.33-7.30 (to, 2H), 7.24-7.18 (t, 18), 7.08-6.96 (iv, 2H), 6.42 (4 . ,2 Hz by LC/MS: retention time: 23.00 minutes, purity: 93 y, MS (mass/charge): 424 (MH). 7.3.244 sh4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2 - | Analogously to the preparation of 144-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(3-phenyl-5-methylisoxazol-4-yl)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-Stylenedioxyphene yl)-5-fluoro-M2-4(3-pyrimidinediamine (2926743) phenyl-5-methylisoxazol-4-1l)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl) -5-fluoro-4-pyrimidinamine and 5-methyl-3-phenyl»-4-isoxazolamine. LC/MS: retention time: 29.90 minutes; purity: 96 99;

MC (mass/charge): 420 (MN.Yu). 7-3.245 Ma-(3,4-styrenedioxyphenyl)-5-fluoro-M2- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(3,5-dimethylisoxazol-4-yl) )-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-ethylenelioxyphenyl)-5-fluoro-M2-(3,5-pyrimidinediamine (926744) dimethylisoxazol-4-yl)-2,4 -pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3,5-dimethyl-4-isoxazopamine. LC/MS: retention time: 18.89 minutes; purity: 98 55; MS (mass/charge): 3585 (MIN). 737246 m2-p- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(thoxycarbonylmethylenethio)pyridine «5-0 | hydroxyphenyl)-2,4-pyrimidinediamine, M2-12-(thoxycarbonylmethylenethio )pyridine - yl|-M4-(3,4-styrenedioxyphenyl)-5-fluoro-5-yl|-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained in 2,4- pyrimidinediamine (K926727) resulting from the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 5-amino-2-(ethoxycarbonylmethidentio)pyridine, 1H NMR (0M50-46): g 9, 30 (5, sem 1H), 9.22 (in, 1H), 8.62 (0, 1H, 3- 2.4 Gy), 8.06-8.01 (t, 2), 7.25 ( 4, 18, 1-: 2.4 Gy), 7.18-7.14 (t, 2H), 6.89 (9, 1, 22: 6.0 C), 4.22 (08, 4H) , 4.07 (9, 2H, 34- 6.9 Gy), 3.95 Ge) (Se) (22) che s so - . and? so ko -y (Se) (42) ko 60 b5

(5, 2H), 1.14 (5 ZN, 7: 6.9 Hz); LC/MS: retention time: 21.60 minutes; purity: 97 55; MS (mass/charge): 458(IMN). 7.3.247 Mm2-(2- Analogous to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3- (stoxycarbonylmethyleneoxy)pyridine -5- 1 hydroxyphenyl)-2,4-pyrimidinediamine, M2-|2 -(ethoxycarbonylmethyleneoxy)pyridine-yl|-M4-(3,4-etiphenedioxyphenyl)-5-fluoro-Ada (3 4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine was obtained in 2,A-pyrimidinediamine (KU26740) as a result of the reaction 2-chloro-M4-(3,4-ethylenelioxyphenyl)-5-fluoro-4-pyrimidinamine and 5-amino-2-(ethoxycarbonylmethyleneoxy)pyridine. 1 NMR (0ЮМ50-46);: GI 9.54 (bv, 18 ), 9.14 (b, IN), 8.05 (5, IN), 7.88 (a, 1H, Re 2.4 Hz), 7.54 (ai, 1H, 1: 2.7 and 10 ,2

Hz), 7.22(6.1H, 2125 8 Gy), 71044, 1H, 12 1.8 and 8.7 Hz), 5.75 (d, 1H, He 9.0 Go), 6.80 ( y, IN, 1 9.9 Gy), 4.55 (5, 21), 4.20 (5, 4H), 4.10 (4, 2H, 72: 7.2 Gy), 1.18 ZN,

Ing72 gy). 7.3.248 5-bromo-M2-(3,4-ethylenedioxyphenyl)-M4- | Similarly to the preparation of M4A-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(3-hydroxyphenyl)-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, 5-bromo-M2-(3, 4-ethylenedioxyphenyl)-M4-(3-(K925797) hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-bromo2-chloro-M4-(3-hydroxyphenyl)-4-pyrimidineamine and 3,4-styrenedioxyaniline. IN NMR (SOSIS): 0 9.33 (5, 1H), 9.06 (5, 1H), 8.34 (5, 1H), 8.14 (5, 1H), 7.13-7.06 -(t, 4H), 6.94 (B5, 17), 6.61 (d, IN, 12 8.7 Gy), 6.54-6.50 (t, 1H), 4.17-4, 13 (t, 4H); RHU/MS: retention time: 20.01 minutes; purity: 93 95; MC (mass/gross); 416 (MNE). 7.3.249 742-allyl-5-bromo-M4-(3-hydroxyphenyl)- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-2,4-pyrimidinediamine (K925822) hydroxyphenyl) -2,4-pyrimidinediamine, M2-allyl-5-bromo-M44(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-bromo-2-chloro-M4-(3-hydroxyphenyl)-4- pyrimidineamine and allylamine. 1 NMR (SOZOI: HI 8.08 (5, TN), 721 (B1Н, 1-8 Gy), 7.02-6.97 (t, 2Н), 6.71 (99, 1Н, 1-2, 4 and 8.7 Hz), 5.91-5.77 (t, IN), 5.19-5.09 (t, 2H), 3.94-3.89 (t, 24); LC/MS : retention time: 18.33 minutes; purity: 99 95; MS (mass/charge): 322 (MINu). 7.3.250 5-cyano-M2-(3,4-ethylenedioxyphenyl)-M4- Similar to the preparation of M443,4-ethylenedioxyphenyl )-5-fluoro-M2-(3-(methoxycarbonylbenzyl)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, 5-cnan-M2-4(3,4-ethylenedioxyphenyl)-M4-pyrimidinediamine (K925820) ( methoxycarbonylbenzyl)-2,4-pyrimylinliamine is obtained as a result of the reaction of 2-chloro-5-cyano-ych4-methoxycarbonylbenzyl)-4-pyrimidineamine and 3,4-ethylenedioxyaniline. IN NMR (SOSIZU: GP 8.23 (5, 1), 7.41-7.32 (t 58), 7.01 (4,

IN, I- 3.0 Hz), 6.86-6.71 (to, ZN), 6.54 (05, 1H), 5.48 (y, IN, 1-63 Hyd), 4.31 ( 65, 4H), 3.98 (5, ЗН); EX/MS: retention time: 25.53 minutes; purity: 97 90; MS (mass/charge): 418 (MNK). with

Analogous to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-ethoxycarbonyl(dimethyl)methyl|phenyl-hydroxyphenyl)-2,4-pyrimidinedismine, M4-14-he) (Ce) (22) che s so

M2-(3,4-Stylenedioxyphenyl)-5-fluoro-2,4- | |stoxycarbonyl(dimethyl)methylphenyl|-M2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine pyrimidinedigmine is obtained as a result of the reaction of 2-chloro-M4-14- shsh

Ethoxycarbonyl(dimethyl)methylphenyl|-5-fluoro-4-pyrimidinamine and 3,4-s ethylenedioxyniline. IN NMR (0M5O-4d6): (9.31 (z, 1NI), 8.97 (5, 1H), 8.03 (4, 18, 153.5 Sv), 7.70 (a, 2H, 1 -88 Go), 7.294, 1.7: 2.3 Gy), 7.23 (4, 2H, 1 - 8.8 Go), h - 6.98 (ad, H, 1-21 and 8.8 Gy) , 6.664, 1H, / - 8.2 Hz), 4.19-4.15 (t, 48), 4.07 (di, k ?H, 17.0 Hz). 1.48 (5.6HB BIO (i, ZN, 1: 7.0 Go). LC/MS: retention time: 24.51 minutes; purity: 10095; MS (mass/charge): 453 (MIN). 7.3 .252 (8935173): M2-(3,4 ethylenedioxyphenyl)- | Similar to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-fluoro-M4-H4(2-hydroxy. 5-fluoro-M4-14402-hydrokei- ,1- 11-dimethylethyl)phenyl)-pyrimidine-2,4-diamine, M2-(3,4-styrenedioxyphenyl)-5-fluoro-(ee)dimethylethyl)phenyl)-2,4-pyrimidinediamine | M4-(14-(2-hydroxy-I, I-dimethylethyl)phenyl|-2.4-pyrimidinediamine is obtained as a result of the reduction of M4-14-Ethoxycarbonyl(dimethyl)methyl|phenyl)-M2-(3,4-

KkZz ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinedigmine with the help of diisobutylpuminiitride OIVASN. IN NMR (0M50-46): HP 9.23 (5, 1H), 8.94 (5, - 1NU, 8.01 (4, 1H, 32: 3.5 Hz), 7.63 (a, 2H , 7 2 8.8 Gy), 7.31-7.27 (t, ZN), 6.98 (da, IN, 122.9 and 8.8 Gy), 6.65 (8, 1H, 5 2 : 8.8 Hn), 4.65 (i, TN, 3 - 5.3 Hn), 417-416 (t, 4H), 3.39 (8, 7H, 3: 5.2 Gy), 1, 20 (5, 5H). 8.9 Hz), LC/MS: retention time: 19.52 (se) minutes; purity: 10095; MC (mass/charge): 411 (MN). 7.3.253 8915182. pyrimidinediamine, 5-feoro-M2-(|4-

Ma-(3,4-propylenedioxyphenyl)-2,4- (methoxycarbonylmethyleneoxy)phenyl|-M4-(3,4-propylenedioxyphenyl)-2,4- pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fucor-M44( 3,4-propylenedioxyphenia)-4-pyrimidinamine and 4-(methoxycarbonylmethyleneoxy aniline.

IN NMR (0M50-4y6): (19.16 (8, 1H), 9.01 (5, 1H)), 8.104, 1H, 224.1 Gy), 7.51 (a, 2H, 1-88 Ho ), 7.37 (y, YIN, 1: 2.9 Gy), 7.32 (0, YIN, 2: 2.9 and 8.8 Hz), 6.98 (0, 1H, 22 8.3

ГИ), 6.80 (4, 2Н, 1: 8.3 Ги), 4.70 (5, 2Н), 4.12-4.05 (arr di, 4Н, 2»: 5.3 Го), 3.68 (in,

HF) ZNO, 2.07 (а, 2Н, 1-5.3 Gy), РЧ/MS: duration of retention; 20.51 minutes; purity: 9795; MC (mass/charge): 441 (Mn). le 7.3.254 2935185: 5-ftar-M2-13- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(methoxycarbonylmethyleneoxy)phenyl-hydroxyphenyl)-2,4-pyrimidinediamine, 5 -fluoro-M2-|3- in Ma-(3,4-propylenedioxyphenyl)-2,4- (methoxycarbonylmethylethoxy)phenyl|-M4-(3,4-propylenedioxyphenyl)-7,4- pyrimidinediamine pyrimidinediamine is obtained as a result of reaction 2 -chloro-5-fluoro-M4-(3,4-propylenedioxyphenyl)-4-pyrimidinamine and 3-(methoxycarbonylethyleneoxy)aniline.

IN NMR (OM850-4y6y: I 9.22 (5, 1H), 9.18 (5.1), 8.07 (8, 1H, 3- 3.5 Go), 7.41-7.35 ( t, 2), 7.32-7.28 (t, 2NI), 7.09 (i, IN, 22 8.2 Gy), 6.90 (4, EN, 3- 8.2 Hz), 6.43 (44, and 1H, 3-2.3 and 8.8 Hz), 4.65 (5, 2), 4.11-4.04 (arr d, 4H, 7- 5.3 Hz), 3, 67 (8, ZN), 2.06 b5

III (a, 2H, 1-2 5.3 Gy); LC/MS: retention time: 20.57 minutes; purity: 9755; MC (mass/charge): 441 (MN). 7.3.255 Ko935187: M4-I34(1- Analogously to the preparation of h4-(3,4-ethylenedioxyphenium)-5-fluoro-M2-(3-bis(ethoxycarbonyl)ethoxy)phenyl|-5-hydroxyphenyl)-2,4- pyrimidinediamine, M4-|3-(1-bis(ethyloxycarbonyl)ethoxy)phenyl)-fluoro-M2-(4-isopropoxyphenyl)-2,4-5-fluoro-M2-14-isopropoxyphenyl)-2,4-pyrimidinediamine pyrimidinediamine as a result of the reaction of 2-chloro-5-fluoro-M-(4-isopropoxyphenyl)-4-pyrimidinamine and 3-(1-bis(stoxycarbonyl)ethoxy|aniline. 1H NMR (OM 5О0-а6у: 17 10.08 ( 5, 1), 9.98 (in,

IN), 8.19 (40, 1H, 2-2 4.7 Gy), 7.55 (4, 2H, 1- 8.8 Hn), 7.254, 1H, 1- 8.8 Ha), 7.154

IN, -83 Hz), 713 (4, 1H,3- 8.3 Hz), 6.91 (8, 2H, /- 8.8 Hz), 6.51 (44, 1H, 12 1.7 and 8.3 Hz), 4.56 (4, 1H, le 5.8 G1d), 4.19 (di, 4H, 1-:7.0 Gu), 1.61 (5, ЗН), 1.23 (4, 6H, 12 5.8 Hu, 114 (i, 6H, 1- 7.0 Hz); LC/MS: retention time: 15.23 minutes; purity: 9425; MS (mass/charge): 527 ( МН). 7.3.256 K915190: MA-(3,4-ethylenedioxyphenyl)-5- -yl)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, IR4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-pyrimidinediamine (indazolin-b-yl)-2,4-pyrimidinediamine is obtained as a result reactions of 2-chloro-M-43,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and b-aminoindazole, IN NMR (PMO-46): (19.69 (in, TN), 9.62 (in, PN), 8.14 (4, MN, 3-4.7 Gy), 7.93 (5, IN), 7.92 (5,

IN 7.60 (0, IN, 2-8.8 Hz), 7.33-7.31 (t 18), 7.24 (49, H, 1 1.7 and 8.8 Gh), 6, 79 (4, 1-2 8.8 Hz), 4.20 (5, 4H); LC/MS: retention time: 17.66 minutes; purity: 9990; MS (mass/charge): 379 (MNE) 19 7.3.257 K915191: 5-fluoro-M4-(3-tihydroxyphenyl)- Similar to the preparation of M4-4(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3 -

M2-(indazoline "6-ip)-2,4-pyrimidinediamine | hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro M44(3-hydroxyphenyl)-M2-(indazoline - 6-yn)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M-(3 - hydroxyphenyl)-4-pyrimidicamine and 5-aminoindazole. 1H NMR (0M50-46): 19.74 (5, 1H), 9.66 (5, 1H), 8.18 (0, 1H, 1-2 41 P), 7.95 (in, 18, 7 .93 (5, 1H), 7.59 (y, IN, 7-8.8 Gy), 7.33-7.26 (t, 2H)), 7.12-7.07 (t, 2H) , 6.52 (dd, 1H, 7-2 2.3 and 8.2 Gy); RHU/MS: retention time: 15.27 minutes; purity: 9995; MS (mass/charge): 337 (МНА 7-3.254 КО35193: М4-(3,4-styrenedioxyphenyl)-5- | Similar to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-Fluoro-M2-(3- fluoro -M2-(t-methyl-indazolin-5-yl)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(1-pyrimidinediamine methyl- indazolin-5-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5"fluoro-M-(3,4-ethylenedioxyphenyl)-4-pyrimidinamine and i-methyl-5-aminoindazole.

IN NMR (0M50-46u: (110.42 (5, 2H), 8.25 (4, 1H, 1- 5.2 Gy), 7.92 (in, 1H), 7.86 (arr 8.1 ), 7.618, 1Н, 1-8.8 Hz), 7.38 (40, 1Н, 3-23 and 9.3 Gy), 7.21 (0, 1Н, Re 2.3 Gy), 7.09 ( 94, EN, 2-7.3 and 8.8 Gy). 6.79 (0, 1H, 72 8.8 Hz), 4.20 (5, AN), 4.02 (v, ZM); se

LC/MS: retention time: 19.09 minutes; purity: 9995; MS (mass/charge): 393 ni PPO VN KZ: VINO UNO OO Ov o 7.3.759 KoO35194: 5-fluoro-M4-(3-hydroxyphenyl)- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro -M2-(3-

М24(1-methyl-indazolin-5-yl)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-м4-(3-hydroxyphenia)-М2-(1-methyl-pyrimidinediamine indazolin-5- yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-3-fluoro-M-(3-hydroxyphenyl)-4-pyrimidinamine and 1-methyl-5-aminoindazole. IN NMR «se (OM50-46): С 10.56 (5, IN), 10.49 (5, 18), 8.29 (4, 1Н, 1- 5.2 Hz), 7.980, 1Н,3 -1.7

Ahem). 7.92 (5, 1H)U, 7.59 (4, 1H, 7-8.8 Hn), 7.3644, 1H, 12: 1.7 and 8.8 Gy), 7.10 (bg t ,

ZN), 6.66 (ID, IN, 21- 1.7 and 7.0 Go), 4.01 (5, ZN). PH/MS: retention time: b» 16.62 minutes; purity: 9895; MC (mass/charge): 351 (MN). 1.3.260 K935197: 5-fluoro-M2-(indazolin-5-yl)- Similar to the preparation of IM4-4(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- «--

M44(4-isopropoxyphenyl)-2,4-tihydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-M2-(indazoline-5-17)-M4-(4-pyrimidinediamine isopropoxyphenyl)-2,4-pyrimidinediamine are obtained in as a result of the reaction of 2-chloro-5-se fluoro-M-(4-isopropoxyphenyl)-4-pyrimidinamine and 5-aminoindazoline. IN NMR (pM5O-4a6): P 9.96 (5, 1H)), 9.76 (in, IN), 8.17 (4, 1H,, 15: 4.6 Hu), 7.94 (5 , 1H), 7,925, o

IN), 7.53 (4, 2H, 1: 9.8 Hz), 7.46 (4, 1H, 3 8.8 Gy), 7.34 (40, IN, I- 1.7 and 9, 8 Hz), 6.83 (4, 2H, 12: 9.8 Gy), 4.55 (9, 1H, 12 5.8 Gy), 1.24 (y, 6H, 1- 5.8 Gy) . LC/MS: retention time: 18.96 minutes; purity: 10099; MS (mass/charge): 379 (MA t). 7.3.261 K935198: ШЧМ4-(3,4-ethylenedioxyphenyl)-5- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-fluoro-M2-(indazolin-5-1l)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3 ,4-ethylenedioxyphenyl)-5-fluoro-M2- « pyrimidinediamine (inlazoline-5-1l)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M-(3,4-ethylenedioxyphenyl)-4 -pyrimidinamine and 5-aminoindazole. IN NMR shsh (0M5O-46): 1 9.91 (5, IN), 9.82 (in, IN), 8.13 (4, 18, 4- 4.6 Gy), 7.94 (arr 5 . 71344, 1H, 72.3 and 8.8 Hz), 65.76 (4, 1H, 32 8.8 Hz), 4.20 (in, 4H); PH/MS: ; with" retention time: 16.17 minutes; purity: 9995; MC (mass/charge): 379 (MN). 7.3.262 K935199: 5-fluoro-M4-(3-hydroxyphenyl)- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-43-142-(indazolin-53-yl)-2,4 -pyrimidinediamine | hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-IM4-(3-hydroxyphenyl)-M2-(indazolin-5-yl)-2,4-pyrimidinediamine are restrained as a result of the reaction of 2-chloro-5-fluoro-M- (3-hydroxyphenyl)-4-pyrimidinamic and 5-aminoindazole. 1H NMR (M 50-46): 119.78 (og) (5, 1H), 9.68 (5, IN), 9.49 (bBg5, IN), 8.13 (4, 1H, 1-4 ,6 Gy), 8.06 (5, 1H), 7.93 (5, IN), 7.500, 1H,3- 8.8 Hz), 7.38 (4, 1H, 1: 1.7 and 8 .8 Hz) 7.17 (f 1H, 2-82 Hz), 711- ko 7.06 (tp, 2H), 6.57 (44, 1H, 1-.1.4 and 8.2 Gy). LC/MS: retention time: 13.79 minutes; purity: 9695; MC (mass/charge): 337 (MN). - 7.3.263 K935203: 5-fluoro-M2-(4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-m2-(3- isopropoxyphenyl)-M4-(1-methyl-hydroxyphenyl)-2 ,4-pyrimidinediamine, 5-fluoro-M2-(4-isopropoxyphenia)-Mm4-(1-(Ce) 42)

F) ko 60 b5 indazolin-5-yl)-2,4-pyrimidinediamine methyl-indazolin-5-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-IM-(1-methyl- indazolin-5-yl)-4-pyrimidinamine and 4-isopropoxyaniline. IN

NMR (OM5O-46: (110.57 (5, 1H)), 10.12 (8, 1H), 8.24 (y, 1H, 3-5.3 Gy), 8.04 (5, IN) , 7.95 (5, IN), 7.63 (4, IN, 12 9.3 Hz), 7.55 (440, IN, 1: 1.7 and 8.8 Hz), 7.30 (d , 2H, 1: 9.4

Hy), 6.82 (6, 2H, P- 8.8 Hyd), 4.53 (9, 1H, 32 6.4 Ky), 2.02. (5, ZN), 1.22 (4, 62, 1-64

Gi). LC/MS: retention time: 20.56 minutes; purity: 9995; MS (mass/charge): 393 (MNY). 7.3.264 K935204: 5-fluoro-M2-(3-hydroxyphenyl)- Similar to the preparation of M443,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-

Ma-(1-methyl-indazolin-5-yl)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-I42-(3-tihydroxyphenyl)-M4-I1-methyl-nyrimidinedigmine indazolin-5- yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M(1-methyl-indazolin-5-yl)-4-pyrimidinamine and 3-aminophenol. LC/MS: retention time: 15.55 minutes; purity: 9825; MC (mass/charge): 351 (MN). 7.3.265 8935207: M4-(3,4-ethylenedioxyphenyl)-5- | Similarly to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-fluoro-M2-13-(2-methoxycarbonyl-fur-4-tihydroxyphenia)-2.4-pyrimylidenediamine, M4-(3,4- stylenedioxyphenyl)-5-fluoro-M2-H3-(2- iia)methyleneoxyphenyl)-2,4-methoxycarbonyl-fur-4-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine is obtained in pyrimidinediamine as a result of the reaction of 2-chloro-M- (3,4-ethylenedioxyphenia)-5-fluoro-4-pyrimidinamine and 4-(4-aminophenoxystil)-2-methoxycarbonyl-furan, IN NMR (ЮМ 50-46): 119.48 (5, 1Н), 9, 41 (5, 1H), 8.08 (9, 1H, 1 3.4 Hz), 7.37-7.10 (t, 6H), 5.74 (4, 2H, 1- 8.2

Gi), 6.61 (0, 1H, 2-8.2 Hz), 5.00 (5, 280), 4.19 (yg 5, AN), 3.79 (v, ZN). "X/MS: retention time: 22.85 minutes; purity: 9725; MS (mass/charge): 493 (MNK), 7.3.266 935208: M4-(3,4-ethylenedioxyphenyl)-5- | Similar to the preparation of M4 -(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-for-M2-11 "methoxycarbonyl)methyl"tihydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-ethylenedioxyphenyl)-5-fluoro -M2-(1-indazolin-b-yl|-2,4-pyrimidinediamine (methoxycarbonyl)methyl-indazolin-b-yl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-IM-( 3,4-ethylenedioxyphenyl)-4-pyrimidinamine and b-amino-1-(methoxycarbonyl)methyl-indazoline. 08 (4, IN, 2: 3.5 Hn), 7.95 (8, IN), 7.918, 1), 7.56 (8, 1H, 1-8,

Go), 7.329, 2H, 8.9 Go), 7.22 (44, 1H, 122.9 and 8.2 Hz), 5.78 (9, 1H, 1-8.8 Gy), 5.06 (5, 2H), 4.21 (5, 4H), 3.61 (5, ЗН). LC/MS: retention time: 19.39 minutes; purity: 9395; MS (mass/charge): 451 (MIN-K). 7.3.207 8935209: 5-fluoro-M2-(4- Similar to the preparation of M44(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(methoxycarbonylethyleneoxy)phenyl-hydroxyphenyl)-2,4-pyrimidinediamine, 5- fluoro-M2-(4-

M44(1-methyl-indazolin-5-1l)-2,4- (methoxycarbonylmethyleneoxy)phenyl|-M4-(1-methyl-indazolin-5-yl)-2,4- pyrimidineliamine pyrimidinediamine is obtained as a result of the reaction of 2-chloro -5-fluoro-M-(1-methyl-Ha indazolin-5-yl)-4-pyrimidinamine and 4-(methoxycarbonylmethyleneoxy)aniline. 1N

NMR (YUM50-46): 79.31 (5, IN), 8.99 (5, 1NU, 8.17 (z, IN), 8.024, 1Н, 2- 3.5 Si), Ge) 7.92 (5 . 1), 7.59 (5, 2H), 7.50 (4, 2H, 1: 8.8 Hz), 6.73 (90, 2H, 7 8.8 Gy), 4.69 (in, 2H), 4.05 (5, ZN), 3.68 (z, ZN). LC/MS: retention time: 17.60 minutes; purity: 9995; MS (mass/charge): 423 (MIN). 7.3.268 8935214: 5-fluoro-M2-(3,5- Analogous to the preparation of IM4-(3,4-ethylenedioxyphenyl)- 5-fluoro-M2-(3. (Che) dimethoxyphenyl)-MM-(1-methyl- indazolin-|hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-M2-4(3,5-dimethoxyphenyl)-M441-5-yl)-2,4-pyrimidinediamine methyl-indazolin-5-yl)-2, 4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-b 5-fluoro-M-(1-methyl-indazolin-5-yl)-4-pyrimidinamine and 3,5-dimethoxyaniline. 1N

NMR (0M5O-46): 179.34 (5, 1H), 9.09 (5, 1A), 8.20 (y, 1H, 1: 5.3 Hz), 8.07 (a, 1H, 3 - 3.5 Gy), 7.90 (in, 18), 7.53-7.55 (t, 2NI), 6.89 (d, 2H, 1- 1.7 Gy), 6.02, IN , 72 2.3 credits:

Hz), 4.02 (5, ЗН), 3.54 (5.6Н). LC/MS: retention time: 18.81 minutes; purity: 9790; MS (mass/charge): 395 (MN). Ha 7.3.269 Ko35215: 5-fluoro-M4-(3-hydroxyphenyl)- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M24(3-

35 M2-(1-(methoxycarbonyl)methyl-hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-MA-(3-hydroxyphenyl)-M2-(1-(ee)indazolin-b-yl|-2,4 -pyrimidinediamine (methoxycarbovyl)methyl-indazolin-6-yl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M-(3-hydroxyphenyl)-4-pyrimidineamine and 6-amino-1-( methoxycarbonyl)methyl-indazoline, LC/MS: retention time: 16.05 minutes; purity: 9095; MS (mass/charge); 408 (MN of egg). 7.327170 K935218: 5-fluoro-M2-(4- Analogous to the preparation of IM4 -(3,4-ethylenedioxyphenyl)-5-fluoro-M24(3-" isopropoxyphenyl). M4-(1-hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-m2-(4-isopropoxyphenyl) M4-11- ( methoxycarbonyl)methyl-indazolin-b-yl- | (methoxycarbonyl)methyl-indazolin-b-yl)-2,4-pyrimidinediamine is obtained in 2 2,A-pyrimidinediamine as a result of the reaction of 2-chloro-5-fluoro-M-11- (Methoxycarbonyl)methyl-indiazolin-b-yl|-4-s pyrimidinamine and 4-isopropoxyaniline 1 NMR (OM5O-46): (19.47 (in, IN), 5.99 (5, 1H), 8, 10 (5, 1), 8.07 (0, 1H, 424.1 G1u), 8.02 (5, 18), 7.68 (8, 18, 38.8 Gi), 7.50- "» 7.46 (t, ZN), 6.74 (0, 2H, 8.8 Hn), 5.26 (5, 2), 4.47 (4, IN, 3 : 5.8 Gy), 3.62 (5, Z), n 1.21 (d, 6H, 2- 5.8 Gy). LC/MS: retention time: 21.76 minutes; purity: 9795; MS (mass/charge: 451 (M). 7.342271 K935219: M2-(3,4-ethylenedioxyphenyl)-5- | Similar to the preparation of 144-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- fluoro- ma-GI "(methoxycarbonyl)methyl-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(3,4-etiphenedioxyphenyl)-5-fluoro-M4-Y- (o c indazolin-b-yl|-2,4- Pyrimidinediamine (methoxycarbonyl)methyl-indazolin-6-yl-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M-|1-(methoxycarbonyl)methyl-indazolin-b-yl|-4-pyrimidinamine and 3,4-ethylenedioxyaniline. 1H NMR (PM5O-46): (19.48 (5, 18), ko 9.01 (5, IN), 8.10 (5, 1), 8.09 (4, 19, 12: 3.5 Hz), 8.01 (v, NN), 7.68 (4, 1H, 7-8.8 Gy), 7.48-7.A3 (t, 1H), 7, 29 (0, 1H, 1: 2.3 Hyd), 6.994, 1H, /- 2.3 and 8.2 G i), 6.67 (09.1, shk 1-23 and 8.8 g), 5.27 (5, 2H), 4.15 (5, 4H), 3.62 (z, ZN). LC/MS: retention time: 18.99 minutes; purity: 9395; MS (mass/charge): 451 (MN). (Se) 42) ko 60 b5

7.3.272 K935220: 5-fluoro-M2-(3-hydroxyphenyl)»- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)- 5-fluoro-M2-(3-

MA (Methoxycarbon)methyl-hydroxyphenyl)-2,4-thyrimidinediamine, 5-fluoro-M2-(3-hydroxyphenyl)-MA4(1-indazolin-b-yl|-2,4-pyrimidinediamine (methoxycarbonylmethyl-indazolin-6- yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M-|14(methoxycarbonyl)methyl-tndazolin-b-yl|-4-pyrimidinamine and 3-aminophenol. : H19.51 (5, 1H), 9.19 (5, 2 IN), 9.105 5, IN), 8.21 (5, 1H), 8.12 (y, 18, 1- 3.5 Hn) , 8.02 (z, 1H), 7.68 (y, IN, 2- 8.8

Se), 7.49-7.45 (t 1), 7.16 (5, 1H), 7.09 (y, IN, 1 7.6 Gy), 6.95 (arry, 1H, 72 7, 6 and 8.2 Hz), 6.31 (49, IN, 3rd, 7 and 7.6 Hz), 5.29 (5, 2H), 3.62 (5, ЗН). VH/MS: retention time: 16.16 minutes, purity: 9795, MS (mass/charge): 409 (MN). 7.3.273 M4-(3,4-ethylenedioxyphenyl)-M2-(3- Analogous to the preparation of M4-(3-zaminophenyl)-M2-(2-(methoxycarbonyl)- furanylmethylene)-5-fluoro-2,4- benzofuran- 5-yl)-5-fluoro-2,4-pyrimidinediamine, 44-(3,4-ethylenedioxyphenyl)-m2-(3-pyrimidinediamine (29502033 furaniamethylene)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of reaction 7 - chloro-M4-(3,4-ethylenedioxyphene p)-5-fluoro-4-pyrimylamine and 3-aminomethylenefuran. LC/MS: retention time: 19.99 minutes; purity: 88.45; MS (mass/charge) : 343.07 (МНЕ. 7.3.274 Ма43,4-ethylenedioxyphenyl)-5-fluoro-М2» Analogous to the preparation of М4-(3-aminophenyl)-М2-(2-(methoxycarbonyl)-(α-methoxyphenoxy)stil) -2,4- benzofuran-5-yl|-5-fluoro-2,4-pyrimidinediamine, M4-(3,4-ethylenedioxyphenyl)-5-pyrimidinediamine (K950204) fluoro-M2-((4-methoxyphenyloxy)ethmyl- 2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 2-(4-methoxyphenyloxy)ethylamine. LC/MS: retention time: 22.74 minutes, purity: 91.95, MS (mass/charge): 413 ,05 (MNK). 7.3.275 M2-12,3-dihydrobenzo| bifurane5- Analogous to the preparation of M4-(3-aminophenyl)-M2-(2-(methoxycarbonyl)-ylmethyl-M4-4(3,4-ethylenedioxyphenyl)-5- | benzofuran-5-yl1-5-fluoro-7,4 -pyrimidinediamine, M2-(2,3-dihydrobenzo|BIfuran-5-fluoro-2,4-pyrimidinediamine (K950205) ylmethyl|-M4-4(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine are obtained as a result of the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamic and 2,3-cyhydrobenzoic 5|furan-5-ylmethylamine LC/MS: retention time: 21.43 minutes; purity: 97.59; MS (mass/charge: 395.05 (MIN. 7.3.276 Х2-(2,3-pyhydro-!4-benzodioxin-2-) Analogously to the preparation of М4-(3-aminophenyl)-М2-/ 2-(methoxycarbonyl)-ylmethyl)-M4-(3,4-ethylenedioxyphenyl)-5-|benzofuran-5-yl|-5-fluoro-2,4-pyrimylidenediamine, M2-(2,3-dihydro-1, 4-benzodioxin-fluoro-2,4-pyrimidinediamine (K950206) d-ipmethyl)-M-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3 ,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine. LC/MS: tr retention time: 22.49 minutes; purity: 87.69; MS (mass/charge): 411.01 MNE). sem 7.3.277 Ma-(3,4-ethylenedioxyphenyl)-3-fluoro-M2- Similar to the preparation of M4-(3-aminophenyl)-M2-|2-(methoxycarbonyl)-2-(methylthio)-I,3-benzothiase -6-ylI-2,4-benzofuran-5-yl-5-fluoro-2,4-pyrimidinediamine, M4-(3,4-styrenedioxyphenyl)-5-o (Ce) (22)

Zo sten - pt pon (ge) pyrimidinediamine (K9502013 fluoro-M2-(2-"mexylto)-1,3-benzothiaz-6-yl|-2,4-pivimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3 ,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 2-(methylthio)-1,3-benzothiazop-b-amine. LC/MS: retention time: 22.67 minutes; purity: 76.995; MS (mass/ charge): 441.94 (MH). 7.3.278 M2-|2,3-dihydrobenzo|B|furan-5- Similar to the preparation of M4-(3-aminophenyl)-M2-(12-(methoxycarbonyl)-" ipmethyl| -5-fluoro-44-(3-hydroxyphenyl)-benzofuran-5-yl)|-5-fluoro-2,4-pyrimidinediamine, M2-12,3-dihydrobenzo|BIfuran-5-2,4-pyrimidinedismine (950213) idlmethyl -z-fluoro-M4-(3-tihydroxyphenyl)-7,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-43-tihydroxyphenyl)-4-pyrimidinamine and 2,3-dihydrobenzo( B|furan-5-yl-methylamine. LC/MS: retention time: 17.80 minutes; purity: 99.25; MS (mass/charge): 353.08 (MH), ; - 7.3.279 M2-( 2,3-dihydro-1,4-benzodioxin-2- Similar to the preparation of MA-(3-aminophenyl)-M2-|2-(methoxycarbonyl)-ylmethyl)-5-fluoro-M 4-(3-hydroxyphenyl)-benzofuran-5-yl)|-5-fluoro-2,4-pyrimidinediamine, 142-(2,3-dihydro-1,4-benzodioxin-2,4-pyrimidinediamine (8950214) 2-iamethyl )-5-fluoro-M44(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of resection of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)y-4-pyrimidinamine and 2,3" dihydro-1 ,4-benzodioxin-2-yl-methylamine. LC/MS: retention time: 19.26 seconds; purity: 95.29; MS (mass/charge): 369.08 (MN). 7.3.280 5-fluoro-M4-(3-hydroxyphenyl)-M2-(2- Similar to the preparation of M4-(3-aminophenyl)-M2-(2-(methoxycarbonyl)- co (methylthio)-1,3-benzothiaz -b-1l)-2,4- benzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, 5-fluoro-Ma-(3-hydroxyphenyl)-MI» pyrimidinediamine (2950212) (2-(methylthio )-1,3-benzothiaz-6-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-3-fluoro-Ma-(3-hydroxyphenyl)-4-pyrimidinamine and 2-(methylthio)-1, 3- -- benzothiazol-b-amine. LC/MS: retention time: 19.83 minutes; purity: 98.99; MS (mass/charge): 399.98 (MN). re) 7.3.281 M2-(3-aminophenyl)-5-fluoro-M4-443- Similar to the preparation of M4-(3-aminophenyl)-M2-12-(methoxycarbonyl)» hydroxyphenyl)-2,4-pyrimidinediamine benzofuran-5 -ylI-5-fluoro-2,4-pyrimidinediamine, M2-(3-aminophenyl)-5-fluoro-Х4-(3-(I (5950227) hydroxyphenyl)-2,4-pyrimidinedismine is obtained as a result of the reaction of 2-chloro -5-fluoro-

Ma-(3-hydroxypheni l)-4-pyrimidinamine and I,Z-diaminobenzene. LC/MS: retention time: 11.89 minutes; purity: 97.696; MS (mass/charge): 312.05 (MN). 7.3.282 Mm241,4-benzoxazin-b-yl)|-5-fluoro-M443- | Similarly to the preparation of M4-(3-aminophenyl)-M2-12-(methoxycarbonyl)-25 nitrophenyl)-2,4-pyrimidinediamine benzofuran-5-ylI-5-fluoro-2,4-pyrimidinediamine, M2-(1,4- benzoxazin-b-yl)|-5-fluoro- (8950253U MA-(3-nitrophenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-

HF) fluoro-MA-(3-thihydroxyphenia)-4-pyrimidinamine and 6-amino-(,4-benzoxazine, LC/MS: retention time: 18.52 minutes; purity: 99.59; MS (mass/charge) : 382.93

We. t -t pet.

M2-(ethoxycarbonylmethyleneaminophenyl)- | Similar to the preparation of M4-(3-aminophenyl)- M2-(2-(methoxycarbonyl)- 60 b5

5-fluoro-Ma-(3-tihydroxyphenyl)-2,4-benzofuran-5-yl|-5-fluoro-2,4-pyrimidinediamine, M2-pyrimidinediamine (950215) (ethoxycarbonylmethyleneaminophenyl)-5-fluoro-M2-43 -hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-3-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine and 3-ethoxycarbonylmethyleneaminophenylaniline.

LC/MS: retention time: 18.90 minutes; purity: 83.495; MS (mass/charge): 398.06 (MN. 7.3.2854 M2-(ethoxycarbonylmethyleneaminophenyl)- | Similar to the preparation of IM4-(3-aminophenia)-M2-(2-(methoxycarbonyl)-5-fluoro-M4-43- (2-benzofuran-5-1l|-5-fluoro-2,4-pyrimidinediamine, M2-hydroxyethylamino)phenyl|-2,4- (ethoxycarbonylmethyleneaminophenyl)-5-fluoro- M4-13(2-hydroxyethylamino)phenia!» pyrimidinediamine (К950229) 2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine and 3-stoxycarbonylmethyleneaminophenylaniline.

PH/MS: retention time: 16.37 minutes; purity: 78.30; MS (mass/charge: 70 441.03 (MN). 7.3.285 5-cyano-M2-(3-hydroxyphenyl)-M4. Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-( 3-(Methoxycarbonylbenzyl)-2,4-thyloxyphenyl)-2 4-pyrimidinediamine, 5-cyano-M2-(3-hydroxyphenyl)-M4- pyrimidinediamine (K925821) (Methoxycarbonylbenzyl)-2,4-pimimidinidiamine is obtained as a result of reaction 7 - chloro-5-cyano-M4-methoxycarbonylbenzyl)-4-pyrimidinamine and 3-hydroxyaniline. 1H NMR(SOSO): 0 8.27 (5, IN), 7.38-7.28 (t, ZNU, 7.19-7.07 (t, 2H)), 6.98-6.91 ( t, 2H), 6.64 (0, 18, 1: 6.6 ku), 3.55 (8, ZN); LC/MS: retention time: 2418 minutes; purity: 98 29; MS (mass/charge): 376 (MIN). 7.3.286 5-fluoro-M4-42-fluoro-4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- (methoxymethyleneoxy)phenyl|-M2-(3- hydroxyphenyl)- 2,4-pyrimidinediamine, 5-fluoro-M4A-4(2-fluoro-4-hydroxyphenyl)-2.4-pyrimidinediamine methoxymethyleneoxyphenyl)-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained in (K926680) as a result of reaction 2 -chloro-5-fluoro-M4-(2-fluoro-4-methoxymethyleneoxyphenyl)-4-pyrimidinamine and 3-hydroxyaniline. 7.3.287 МА-(3,4-ethylenedioxyphenyl)-5-fluoro-м2- Similar to the preparation of Ма4-(3,4-ethylenedioxyphenyl)-5-fluoro-М24(3-

KIN) indol-d-yl)-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, MA, 4-ethylenedioxyphenyl)-5-fluoro-M2" (К926748) (1 H-indol-5-yl|- 2,4-pyrimidinediamine is obtained by the reaction of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 5-aminoindole.LC/MS: retention time: 20.37 minutes; purity: 97 95; MS (mass/charge): 378 (MH cu). 7.3.288 5-fluoro-M4-(3-kpyroxyphenyl)-M2-C1H)- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro -M2-(3-indol-5-yl|-2,4-pyrimidinidiamine hydroxyphenyl)-2,4-pyrimizindiamine, 5-fluoro-Ma4-(3-hydroxyphenyl)-M2-KI1H)-indole- (8926749) 5 -yl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-1H4-(3-hydroxyphenia)-4-pyrimidinamine and 33-aminoindole. РХ/MS: duration of sem retention: 17.31 minutes; purity: 94 95; MS (mass/weight): 366 (MN k). 7 o 7.3.289 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-3-fluoro-M2-(3-

CIN) indole-b-yl|-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, 1444(3,4-ethylenedioxyphenyl)-5-fluoro-M2- (85926750) And HO-indole-b-yl| -2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-m4-(3,4-ethylenedioxyphenyl)-3-fluoro-4-pyrimidinamine and 6-aminoindole. ERC/MS: retention time: 20.80 minutes; purity: 91 95; MS (mass/charge): 378 (MN.Yu). "se 7,3.290 5-fluoro-M4-(3-hydroxyphenyl)-M2-I H)- Analogous to the preparation of M4-(3,4-etipenedioxyphenyl)-5-fluoro-M2-(3-indol-b-yl| -2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-ShM4-(3-hydroxyphenyl)-M2-C1H)-indole-b (K9267513 6-yl|-2,4-pyrimidinediamine is obtained as a result reactions of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine and b-aminoindole LC/MS: retention time: 18.13 minutes purity: 96 95 MS (mass/charge): 336 (MP). or 7.3.291 Mma-4- Analogously to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-(aminocarbonylmethyleneoxy)phenyl|-5-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(4-(aminocarbonylmethyleneoxy)phenyl|-5-z. fluoro-M2-(3-hydroxyphenyl)-2,4-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (75 mg, 7595) receive in

C5 pyrimidineliamine (К945063) as a result of the reaction of 3-hydroxyanilic (110 mg, ! mmol) and MA-(4-(ee) («aminocarbonylmethyleneoxy)phenyl|-2-chloro-5-fluoro-4-pyrimidinamine (80 mg, 0.27 mmol ).IN NMR (acetone-4dbu: GP 7 4.51 (in, 2 H), 6.64 (dt, 1-8.4 Hz, 1 NU, 7.06-7.14 (t, 5 NU, 7.70 (4, 1: 2.4 and 90 Hz, 2 NU, 8.27 (a, 3- 6.0 Сy, I H); 19E NMR (282

MG, acetone-d6): Si -164.00; LC/MS: retention time: 14.66 minutes; purity: 88.6395; MS (mass/charge): 370.00 (MY). "7.3.292 MA414-(cyanomethyleneoxy)phenyl"-3" Similar to the preparation of MA4(3,4-ethylenedioxyphenyl)-5-fluoro-m2-(3-fluoro-M2-(3-hydroxyphenyl)-24-hydroxyphenyl)-2 "a-pyrimidindiami! willow, 44-14-(pianmethyleneoxy)phenyl!-5-fgor-M2-2 pyrimidinediamine (K945071) (3-hydroxyphenyl)-2,4-pyrimidinediamine (65 mg, 6495) in the form of a solid fraction with sober white color is obtained as a result of the reaction of 3-hydroxyaniline (94 mg, 0.86 mmol) and 2-chloro-Ma-(4-(cyanomethyleneoxy)phenyl|-5-fluoro-4-pyrimidinamine h (80 mg, 9.29 mmol). 1H NMR (acetone-4b): HI 5.16 (5, 2 NU, 6.64 (aa, 7- 1.8; 2.4 and i » 7.5 hz, NN), 7030122 gy, 1 M), 7.08-7.16 (t, 2 Nu), 7.194, 1-93 Hn, 2 NN), 7.77 (4.1-9.3 Hz, 2 H), 8.30 (4.3: 5.4 Hz, 1 H), 10.04 (5, I H, MH), 11.33 (5, 1 H, MH); 192 NM (282 MHz, acetone-d6u; 71 163.52; LC/MS: retention time: 17.08 minutes; purity: 10095; MS (mass/charge): 352.13 (MIN). o 7.3.293 M4-( 3-cyanophenia)-5-fluoro-M2-(3- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- hydroxyphenyl)-2,4-pyrimidinlyamine hydroxyphenyl)-2,4- pyrimidinediamine, 3-aminobenzonitrile (142 mg, 1.2 mmol) and (Кк9451091 2,4-dichloro-5-fluoropyrimidine (109 mg, 0.6 mmol)) form 2-chloro-Ma4-(3-ko cynanphenyl)-5 -fluoro-4-pyrimidinamine (128 mg, 8695) in the form of a white solid fraction. obtained as a result of the reaction of 2-chloro-M4-(3-cyanophenine)-5-fluoro-4-(Ce) 42) with 60 b5 of pyrimidineamine (50 mu, 0.2 mmol) and 3-aminophenol (66 mg, 0, 6 mmol), IN NMR (acetone-dbu: 7 6.48 (444, 7: 0.9; 2.4 and 7.8 Hz, 1 8), 7.100 1-8 Hn, 1 HO), 7.18 (aa, 1-1.2: 2.1 and 8.1 Hz, 1 H), 7.33 (62-21 Hz, I H), 7.45 (Fi, 12 1.2 and 7.8 Gy , 1

NU, 7.54 (1281 Hz, 1 NU, 8.08 (0, 3-3.3 Gu, 1 NU, 8.14 (db, 2-1.5; 2.7 and 84 Go, 1

NU 8.39, 2.1 Hz, 1 NU, 8.58 5, 1 N, MN), 8.84 (5, 1 N, MN); 19E NMR (282 MHz, acetone-dbu; CI -167.41; LC/MS: retention time: 17.75 minutes; purity: 92.3990; MS (mass/charge): 322.59 (MN). 7.3. 294 M44(3-cyanophenyl)-5-fluoro-M2-(4- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- methoxycarbonylmethyleneoxyphenyl)-2,2- | ploxyphenyl)-2 . -(3-cyanophenyl)-5-fluoro-4-pyrimidinamine (50 mg, 0.2 mmol) and 4-(methoxycarbonylmethyleneoxy aniline (109 mg, 0.6 mmol). NR NMR "acetone-dbu: 0 3.74 (in, Z H), 4.72 (5, 2 H), 6.93 (y, 1 950 Gy, 2 H)y, 7.46 (4, 7- 1.5 and 7.5 hz,1 NU, 7.54 (0.217, Hz, 1 B), 7.60 (ai, 1- 1.8 and 9.0 Hz, 2 NU, 8.03-8.07 (t, 2

M, 8.43 (tp, 1 H), 8.45 (g, 1 H, MH), 8.80 (g, I NN, MH); 19E NMR (282 MHz, acetone-abu 7 -168.2; LC/MS: retention time: 20.24 minutes; purity: 94.7995; MS (mass/charge): 393.98 (MNK). 7.3.295 5-Fluoro-M4-(3-hydroxyphenyl)-M2-12- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-

Cindol-3-yl)ethyl|-2,4-pyrimidinediamine hydroxyphenia)-2,4-pyrimidinediamine, 5-fluoro-M4-(3-hydroxyphenyl)-M2-(2-(inlol-3" (8945117) yl )ethyl|-2,4-pyrimidinediamine (40 mg, 5399) is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine (50 mg, 0.21 mmol) and tryptamine ( 100 mg, 0.62 mmol). IN NMR (ISOZOBU C 3.01 (27.2 Hz, 2 H), 3.51 0.1:7.2

Ho, 2 H), 6.51 (444, 72: 0.9; 2.1 and 8.1 Gd, 1 NU), 6.96 (20, 7- 0.9 and 7.2 Hu, 1 H ), 703-7.09 (t, 3 NO), 7.22 (4, 3-7.5 Hz, 1 NO, 7.28-7.32 (t, 2 NN), 7.53(6, 5:78 Hz, 1 Nu, 7.72 (4, 15 4.5 Hn, 1 NU; 192 NMR (282 MGu, SOZO); at 171.72, LC/MS: retention time: 20.17 minutes; 95 .6690; MS (mass/charge) in: 364.05 (INN). 7.3.296 5-fluoro-M4-(3-hydroxyphenyl)-M2-(3- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)- 5-fluoro-M2-(3- methoxycarbonylmethyleneoxyphenyl)-2,4-| 2,4-pyrimidinediamine (130 mg) is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-nyrimidineamine (80 me, 0.33 mmol) and 3-methoxycarbonylmethyleneoxyaniline (180 mg, 0 .99 mmol).IN

NMR (acetone-yb); GI 3.74 (5, 3 NU, 4.64 (5.2 N), 6.71 (p 1 N), 6.80 (t 1 N), 7.23-7.32 (t, 6 NU . -3,4-ethylenedioxyphenyl)»5-fluoro-M2- Similar to the preparation of Ma-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- I (3-methoxycarbonylmethyleneoxyphenyl)-hydroxyphenyl)-2,4-pyrimidinediamine . -M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine (80 mg, 0.28 mmol) and 3-methoxycarbonylmethyleneoxyaniline (154 mg, 0.85 mmol). 14

NMR (SRS: O 3.80 (in, UNI), 4.27 (9, 22 0.9 Gy, 4H), 4.58 (5, 2), 6.54 (046, 72: 0.9; 2.1 ha 8.1 Gy, IN), 6.65 (4, 152.7 Hn, IN), 6.86 (0, 1-- 8.7 Gy, 1H), 6.98 (44, 1 2.4 and (Se ) 8.4 Hn, IN), 5.98 (Bg, 1 H), 7.09 (494, 7-2 1.2; 2.1 and 8.1 Hz, IN), 7.18 0.72 : 8., Hz, IN), t24(8, 1-2, hz, 18), 732 (7-2, Gy, 1H), 7.92 (4, 12 3.3 Gy, TM); 19E NMR (282 b

MgHy, SOSIZ p -167.52; LC/MS: retention time: 21.64 minutes; purity: 98.0730; MC (mass/weight): 426.99 (MI). 7.3.298 5-fluoro-M4-(4-isopropoxyphenyl)-M2-(3- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- - methoxycarbonylmethyleneoxyphenyl)-7,4- hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-M4-(4-isopropoxyphenyl)-M2-(3-pyrimidinediamine (К945125) methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (80 mg, 6695) are obtained as a result of the reaction 2-chloro-5-fluoro-ma-(4-isopropoxyphenip)-4-pyrimidinamine (80 g, 0.28 mmol) and methyl 3-aminophenoxyacetate (154 mg, 0.85 mmol). IN YAM (ee) (SRS) Si 1.33 (v, ZN), 1.35 (5, ZN), 3.80 (5, ZNU, 4.52 (r. 2: 6.0 Hz, EN) , 4.55 (5.2H), 6.53 (444, 1- 0.9; 2.4 and 8.1 Hz, IN), 6.59 (4, 2 2.4 Hz, 18), 6 .90 (4, 1-9.0 gy, ZM), 7.04-7.08 (pa, 2NU, 7.16 (5, 32 8.1 gy, IN), 7.32 (2-21 Hz . : retention time: 24.70 minutes; purity: 10095; MS (mass/charge): 427.00 (MNU. « 7.3.299 M244- Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-M2-(3-hydroxyphenyl)) -5- 2 (aminocarbonylmethyleneoxy)phenyl|-5-fluoro-2,4-pyrimidinediamine, M2-|(4-(aminocarbonylmethyleneoxy)phenyl|-5-fluoro-M4-s fluoro-MA-(3-hydroxyphenyl)-2 ,4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (60 me, 4195) is obtained as a result of the reaction of pyrimidinediamine (5945064) with 4-(aminocarbonylmethylethoxy)aniline (198 mg, 1.2 mmol) and 2-chloro-5- fluoro-h4-(3-h hydroxyphenyl)-4-pyrimidinamine (95 mg, 0.4 mmol). IN YAMRE (SOZOB): 7 4.55 (v, i » 2H), 6.75 (at, 22 7 .5 Gy, 1H), 7.08 (d, 29.3 Gy, 2H), 7 ,18 (t, 2H)), 7.22 (4, 158.7 Hz, 1) 7.46 (f,1- 9.0 Hn, NU, 8.09 (9, IN); LC/MS: retention time: 14.38 minutes; purity: 10092; MC (mass/charge): 170.00 (MN.Yu), 7.3.300 5effluoro-Im24(3-hydroxyphenia)- MA-13-(5- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro -M2-(3-o methyl-1,7,4-oxadiazole-3-tihydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-ma-13-(5-methyl-1,2,4 - yl)methyleneoxyphenyl)|-2,4-oxadiazol-3-yl)methyleneoxyphenyl|-4-pyrimidinamine is obtained as a result of pyrimidinediamine (2945132) reaction of 34(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline (499 mg, 2.4 mmol) and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol). 5-fluoro-M2-(3-hydroxyphenyl)"

Ma-(3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl)-2,4-pyrimidinediamine (30 mg, 6295) is restrained as a result of the reaction of 2-chloro-5-fluoro-M4 -(34(5-methyl-1,2,4-(Ce) (42) co 60 b5 oxadiazol-3-yl)methyleneoxyphenyl-4-pyrimidinamine (40 mg, 0.12 mmol) and 3-aminophenol (49 mg 0.36 mmol). , 11), 6.76 (ada, 7- 0.6; 2.4 and 9.0 Hz, 1H), 6.80-6.85 (t, ZNU 712 (1 V hy, MN), 7, 23 (6, 7-2 7.8 Hz, 1), 7.50-7.52 (t, 2H), 7.94 (8, 1- 3.3 Hz, PN), 7.98 s, 3 -2.4 Gu, 1NU; 19E NMR (282 MHz, SSOZI: 7) 167.19; EX/MS: retention time: 18.88 minutes; purity: NObo; MIS (mass/charge): 408.97 (Mn. 73301 М2-(4-(aminocarbonylmethoxy)phenyl|-5- Similar to М4-(3,4-ethylenedioxyphenyl)-5-fluoro-142-(3-fluoro-Ма-(3-(5-methid-1,2, 4-oxadiazol-3-| 2,4-oxaliazol-3-yl)methyleneoxyphenyl)|-2,4-pyrimi dindiamine pyrimidinediamine (2945133) (19 mg, 2492) is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl-4-pyrimidinamine (30 mg, 0.09 mmol) and 4-(aminocarbonylmethyleneoxy)aniline (45 mg, 0.27 mmol). 1H NAM P (acetone-y6): 1; 2.62 (in, ЗН), 4.43 (5, 7Н), 5.19 (5, 2Н), 6.77 (444, з3-1,2; 7.4 and 8.1 g, 1), 6 .94 (4, z- 9.0 Gy, 2H), 7.25 (i, 1e 8.1 Hz, 15), 7.34 (ad, 3: 0.9; 1.8; 9.0 Gy , 15), 7.68 (y, 2: 9.0 gy, 2NU, 7.81 (1-2, Hz, IN), 7.99 (y, 7- 3.6 Gy, IN), 8, 45 (Bg, IN, ME), 8.57 (g,

IN, MNU; 19E NMR (282 MI, acetone-d6u 7 -168.20; LC/MS: retention time: 16.80 minutes; purity: 84.9195; MS (mass/charge); 466.05 (MAK). 7.3.302 Mma-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- ( Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- (3-(5-methyl-1,2, 4-oxadiazol-3-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-styrenedioxyphenyl)-5-fluoro-Y42-13-(5-yl)umethyleneoxyphenyl|-2,4-methyl-1,2 ,4-oxadiazol-3-yl)methyleneoxyphenyl-2,4-pyrimidinediamine (39 mg, 4799) pyrimidineliamine (5945128) is obtained as a result of resection of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4- pyrimidineamine (40 me, 0.14 mmol) and 3-(5-methyl-1,2,4-oxadivzol-3-yl)methyleneoxyaniline (87 mg, 0.42 mmol). 1H NMR (SOSIS): (from 2 ,62 (8, ZN), 4.26 (a.1-21 Hz, 4H), 5.09 (5, 2H), 6.63-6.67 (t, 2H), 6.85 (4, 1: 8.4 Gu, IN), 6, 95-5.99 (t, 2), 7.09 (0, 1-9.9 x 6.9 Gm, 1), 7.19 (6 2- 8.4 Hz, 1), 7.23 ( 4, 1-24 Hz, 1H), 7.42 (0.1: 724 Hn, 1H)), 7.92 (y, 3: 3.0 Hz, 1H); ISE NMR (282 MG, SOSIS); 0 - 167.47; ВХ/МС: duration of retention : 21.25 minutes; purity: 96.7275; MS (mass/charge): 451.01 (MI ku. 7.3.303 5-fluoro-M4-(4-isopropoxyphenyl)-M2-I3- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro- M2-(3-(5-methyl-1,2,4-oxadiazol-3-hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-M4-(4-isopropoxyphenyl)-M2-I34(5-yl)methyleneoxyphenyl -2,4-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine (40 mg, 6390) pyrimidinediamine (K945129) is obtained as a result of the reaction of 2-chloro-5-fluoro-M4 1H NMR (SOSIZU: GI 1.32 (8, ZNU, 1.34 (5, ZNU, 2.61 (5, 3H), 4.52 (p, 326.0 Hz, 1H)), 5.08 (from . ZNO), 7.15 (0.32

YOU Hz, 1), 7.38 (122.1 Hz, 1H)), 7.46 (9, 1»: 9.0 Gy, 2H), 7.91 (4, 1» 3.3 Hn, 18 ; 19E NMR (282 MGy, SOSIZ): P -167.55; LC/MS: retention time: 24.49 minutes; 96.1 590; MS (mass/charge): 451.08 (MN). 7.3.304 M243,4-ethylenedioxyphenyl)-5-fluoro-MA- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-re)

IZ-15-methyl-1,2,4-oxadiazol-3-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(3,4-ethylenedioxyphenyl)-5-fluoro-M4-13-(5-yl)methyleneoxyphenyl| -2,4-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl-2,4-tyrimidinediamine is obtained in (e") pyrimidinelismine (KU45137) as a result of the reaction of 2-chloro-5-fluoro-M4-(3 -(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyphenyl|-4-pyrimidinamine (40 mg, 0.12 mmol) and 3,4-h-:ethylenedioxyaniline (55 mg, 0.36 mmol ). IN NMR (SOSIZU: 01 2.60 (5, ZN), 4.24 (4, 1» 2.7 ha, 4H), 5.21 (5, 2), 6.74-6.78 ( and, 2), 6.81 (4, 12 8.4 Gy, 1H), 6.90 (44, 1- 1,2,7,8 Gu, 1H), 7.01 (id, 1- 2, 4 and 8.4 Gy, 1H), 7.22 (i, 1-: 8.4 Ho, 1H), 7.30 (6, 2» 24 s ha, 1). 7.48 (lg, 18) . 20 minutes; purity: 91.0906; (ee)

MS (mass/charge): 450.99 (MNK). 7.3.305 5-fluoro-M2-(4-isopropoxyphenyl)-m4-(3- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-m2-(3-(5-methyl-1,2, 4-oxadiazol-3-tihydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-M2-(4-isopropoxyphenyl)-M4-13-(5-yl)umethyleneoxyphenia|-2,4-methyl»1,2,4 -oxadiazole-3-1l)methyleneoxyphenite|-2 4-pyrimidinediamine is obtained in pyrimidinediamine (K945138) as a result of the reaction of 2-chloro-5-fluoro-M4-(3-(5-methyl-1,2,4-oxadiazole-3- yl)methyleneoxyphenyl)-4-pyrimidinamine (40 mg, 0.12 mmol) and 4-1isopropoxyanipine (55 mg, 0.36 mmol). 33 (in, in

ЗН), 2.60 (5, ЗН), 4.48 (р, 2- 6.0 Gy, 1Н), 5.20 (5, 2Н), 6.74-6.78 (t, 2Н), 6.87 (9, 71- with 9.0 Hz, 2H), 5.92 (a, 1--1.2 and 8.4 Hz, 1H), 7.22 (.4- 8.4 Hz, 1H), 7.50 (t, ЗН), 7.94 44.2- 3.0 Sn, 2H)U; 192 NMR (282 MHz, SOSIZ): P 168.46; РХ/MS: duration of h with" retention: 24.95 minutes; purity: 73.7475; MS (mass/charge): 451.06 (MN). " 7.3.306 M44(3,5-dimethyl-4-hydroxyphenyl)-5- Using the general hydrogenation conditions, 2,6-dimethyl-2-nitrophenol fluoro-M243- is reduced to 4-amino-2,6-dimethylphenol. Similarly preparation of Ma» methoxycarbonylmethyleneoxyphenial)-2,4-|(3,4-ethylenedioxyphenyl)-5-Fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-pyrimidinediamine (2945139) chloro-M4-(3, 5-Dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidinamine is obtained by reaction of 4-amino-2,6-dimethylphenol (823 mg, b mmol) and 2,4-dichloro-5- fluoropyrimidine (500 mg, 3 mmol) followed by M4-(3,5-dimethyl-4-hydroxyphevyl)-5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenyl)-7,4-pyrimidinediamine (500 mg, ke 5592) obtained as a result of the reaction of 2-chloro-M4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidinamine (500 mg, 1.87 mmol) and 3"-th (methoxycarboniamethyleneoxy)aniline (500 mg , 2.76 mmol).IN NMR (SYUOZOV): S

Y 2.16 (5, 6H), 3.75 (5, 3H), 4.51 (5, 2H), 6.79 (ava, 1-09: 2.4 tav! g, 1, 7.01-7 ,06 (Se) (42) ko 60 b5

(t, 2H), 7.15 (5, 2H). 7.26 (i, 12: 8.1 Su, 1NU, 7.93 (y, 2: 5.7 Sy, 1H); 195 YAM (282

MGn, SVZOr): SE-163.31; LC/MS: retention time: 20.44 minutes; purity: 84.2595; MS (mass/charge): 413.03 (MN). 7.3.307 Ma4-(benzothiophen-3-ylmethyl)-5-fluoro-M2- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(3-hydroxyphenyl)-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, 4-(bexothiophen-3-ylmethyl) -2-chloro-5-fluoro- (8945146) 4-pyrimidinamine is obtained as a result of the reaction of benzothiophen-3-ylmethylamine (244 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.3 mmol). After that,

M-(benzothiophen-3-ylmethyl)-5-fluoro-yl2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mu, 3695) is obtained as a result of the reaction M4-(benzothiophen-3-ylmethyl)-2-hydroxy -5-fluoro-4-pyrimidinamic and 3-aminophenol (200 mg, 1.83 mmol). IN YAMRE (SOSIZ):

Si 4.45 (bg, 1H), 4.95 (44, 1-5 1.2 and 5.4 Hz, 2H), 5.33 (bg, IN), 6.40 (ai, 1-2: 1.2; 2.4 and 8.1 Ha, PV), 6.85 (give, 3: 0.95; 2.1 and 8.1 Hu, 1H), 6.91 (g, 1H), 7.05 (0128, Hz, 1H), 7.26 (t, IN), 7.39-7.47 (t, ZNU, 7.81 (yd, 2- 1.2 and 5.1 Hz, 1H), 7 ,84 (y, 72 3.3 Hn,

IN), 7.92 (t, 1H); I9E NMR (282 MIC, SOSIZ): 0 -168.89; LC/MS: retention time: 21.91 minutes; purity: 99.3495; MS (mass/charge): 365.96 (MEN). 7.3.308 5-fluoro-2-(3-hydroxyphenyl)-Ma4-(3- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-pyridylmethyl)-2,4-pyrimidinediamine hydroxyphenyl )-2,4-pyrimidinediamine, 2-chloro-5-fluoro-M4-(3-pyridylmethyl)-4- 48945147 pyrimidineamine is obtained as a result of the reaction of 3-pyridylmethylamine (162 mg, 1.5 mmol) and 2,4-dichloro -5-fluoropyrimidine (50 mg, 0.3 mmol). After that, 5-fluoro-

M2-(3-hydroxyphenyl)-M4-(3-pyridylmethyl)-2,4-pyrimidinediamic (40 mg, 4390) is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-pyridylmethyl)-4-pyrimidinamine and 3-aminophenol (200 me, 1.83 mmol). IN NMR (SOZOB): 0 AT (5, 28), 6.38 (449, 12:0.9; 2.4 and 8.1 Hz, 18), 6.88 (ad, 120.95 2.1 tav, Hz, 1H), 7.00 (6-8 Hn, 1H), 7.4 (.2- 2.4 Hz, 1), 7.37 (44, where: 4.8 and 7.8 Hz , 183, 7.73 (9.415 3.6 Hz, ENU, 7.87 (461- 21 and 7.5 Hz, 1NI), 8.39 (44, 3- 1.2 and 7.8 Go, 1H) . (mass/charge): 312.05 (MIN). 7.3.309 Ma-(3-chloro-4-hydroxy-5-methylphenyl)-5- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro -M24(3-feoro-M24(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-M4-(3-chloro-4-hydroxy-5-methylphenyl)-methoxycarbonylmethyleneoxyphenyl)-2,4- | 5- fluoro-4-pyrimidinamine is obtained as a result of the reaction of 4-amino-2-chloro-b-pyrimidinediamine (KU45148) with methylphenol and 2,4-dichloro-5-fluoropyrimidine. M4-(3-chloro-4-hydroxy-5-methylphenyl) -5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenia)-2,4-pyrimidinediamine (850 mg, 5599) is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-thiproxy-5-methylphenyl)- 5-fluoro-4-pyrimylinamine with 3-methoxycarbonylmethyleneoxyaniline (1.95 e, 11 mmol). IN NMR (SOZOI): 712.22 se

Nsch that 5, ZI), 3.76 (8, ZNU, 4.52 (in, 2H), 6.50 (f, /- 2.7 and 6.3 Hz, 10), 7.09-7, 14 (t, 2H), 7 t o

T 724.8, NO, 7.303 12 gy, IN), 74944.3-2.3 Hz, YN), 7.884, 3.9

Ha, IN); 192 NMR (282 MGo, SOZOI): 13 -168.70; ВХ/МС: retention time: 29.63 minutes; purity: 98.5695; MS (mass/charge): 432.96 (MH), 7.3.310 ma-K2,5-dimethyl-3-furyl)methyl-5- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2 -(3-fluoro-M2-(3-hydroxyphenia)-2,4- cyproxyphenyl)-2,4-pyrimidinediamine, 2-chloro-M4-1(2,5-dimethyl-3-furyl)methyl)-5- (Che) pyrimidinediamine (4945151) fluoro-4-pyrimidinamine is obtained as a result of the reaction of (2,5-dimethyl-3-fur)methylamine (188 mg, 1.5 mmol) and 2,4-dichloro-5-fluoropyrimidine (50 mg , 0.3 He mmol). After that, M4-1(2,5-dimethyl-3-furyl)methyl|-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (50 mg, 5195) is obtained as a result of the reaction of 2-chloro -M4-((2,5-dimethyl-3-furyl)methyl-5-fluoro-4-pyrimidinamine and 3-che:aminophenol (200 mg, 1.83 mmol). NR NMR (SRSIZ): 0 2.22 (in, ZNU, 2.23 (z, ZN), 4.39 (y0, 7-5.1 Hz, 2H), 5.24 (B, 1H)), 5.90 (5, 15), 6 ... ), 7.71 (t, 2H); I9E NMR (282 MGy,

SOSI3y 0 -167.84; LC/MS: retention time: 19.83 minutes; purity: 96.32959;

MS (mass/charge): 329.05 (MN). (ee) 73.31 Ma-(3,5-dimethyl-4-methoxyphenyl)-5- Similar to the preparation of M2,M4-bis| 3-Methoxy-4-(methoxycarbonyl)phenyl-5-fluoro-fluoro-M2-(3-2.4-pyrimylindiamine, 2,6-dimethyl-1-methoxy-4-nitrobenzene is obtained in methoxycarbonylmethyleneoxyphenyl)-2,4- | as a result of the reaction of 2,6-dimethyl-4-nitrophenol (1.67 g, 10 mmol), potassium pyrimidinediamine carbonate (K945153) (13 g, 0.1 mol) and iodomethane (2.5 ml, 50 mmol). After that, 3,5-dimethyl-4-methoxyaniline is obtained as a result of hydrogenation of 2,6-limethyl-1-methoxy-4-nitrobenzene. Similarly to the preparation of MA-(3,4-ethylenedioxyphenyl)-M2-(3- hydroxyphenyl)-5-fluoro-2,4-pyrimylindiamine, 2-chloro-M4-3,5-dimethyl-4- in methoxyphenyl)-5- fluoro-4-pyrimidinamine is obtained as a result of the reaction of 3,5-s dimethyl-4-methoxyaniline (400 mg, 2.6 mmol) and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol). M4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-M2-3-h methoxycarbonylmethyleneoxyphenia)-2,4-pyrimidinediamine (180 mg, 3599) is obtained as a result of the reaction of 2-chloro-M4-( 3,5-dimethyl-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and 3-(methoxycarbonylmethyleneoxy)aniline (550 mg, 3.6 mmol). IN

NMR (SOZO: 7 2.20 (5, 6H), 3.70 (5, ZY), 3.74 (5, ZNU, 4.52 (v, 28), 6.76 (444, 1: 0, 9; 2.4 and 8.4 Hz, 1), 7.03-7.08 (ta, 28), 7.24 (t, ZN), 7.96 (4, 1-2 5.4 Hz, 13; 19E

NMR (282 MHz, SUOZO): H -1672.92; LC/MS: retention time: 23.13 minutes; (ee) purity: 10095; MS (mass/charge): 427.04 (Mn.V). 7.3.312 ma-(4-(M-benzylpiperazine)phenyl|-МЧ2- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-im2-(3-hydroxyphenyl)-5- ko (3,4-ethylenedioxyphenyl)-5 -fluoro-2,4-fluoro-2,4-pyrimidinamine, M4-14-4(M.-benzylpilerazine)pheny) |-M2-(3,4- pyrimidinediamine (К945155) ethylenedioxyphenyl)-5-fluoro-2, 4-pyrimidinediamine (40 mg, 6395) is obtained as a result of the reaction of MA-1440M-benzylpiperazine)phenyl-2-chloro-5-fluoro-Ya. (Ce) 42) co 60 b5 pyrimidineamine (50 mg, 0.12 mmol) and 3,4-styrenedioxyaniline (0.045 ml, 0.36 mmol). IN NMR (SOSIZ): 1 2.64 0, 4:48 Gy, AN), 3.29 (B, 4- 4.8 Hz, 4H), 3.59 (5, 2H), 4.24 (t , AN), 6.61 (d, IN, MN), 6.68 (be, IN, MN), 6.76 (a, 1- 8.7 Hz, IN), 6.88 (da, 3- 2.4 and 8.7 i, 1H), 6.93 (i, 2- 8.7 Go, 2), 7.19 (a, 1: 2.4 Ga, 1H), 7.28-7, 36 (t, 5H), 7.47 (0.32 8.7 Gy, 2H)), 7.87 (y, 2-3.3 Hz, 1H)); 19E NMR (282 MGy, SOSIZ): r1-168.66; LC/MS: retention time: 18.05 minutes; purity: 10090; MS (mass/charge): 513.10 (MNK), 7.3-.313 fluoro-M2-(3-fluoro-m4-(3-hydroxyphenyl)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-|(2,5-dimethyl-3-furnyl)methyl|-5-fluoro - pyrimidinediamine (K945162) m4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 5996) is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-thihydroxyphenyl)-4-pyrimylamine (50 mg , 0.21 mmol) and (2,5-dimethyl-3-furyl)methylamine (80 mg, 0.63 mmol). 1H NMR (apetone-4dbu: (1 70 2.14 (5, 6H), 4.37 (4, 1 4.2 Gy, 7H), 5.96 (5, 1H), 6.77 (d, 1 - 6.6 Gy, 1H), 7.23-7.28 (t, 28), 7.44 (v, IN), 8.11 (4, 7-48 Gy, 110), 9.05 (ug . mass/charge): 329.98 (MIN). 7.3.314 M2-(4-(M-benzylpiperazine)phenyl|-ma- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3 - 43,4-ethylenedioxyphenyl)-5-fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(4-(M.-benzylpiperazine)phenyl|- M4a-(3,4-pyrimidinediamine) (K945163) ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (39 mg, 3395) is obtained as a result of the reaction of 2-chloro-M44(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinediamine (50 g, 0.18 mmol ) and 4-(4-benzylinperazine)aniline (142 me, 0.53 mmol). IN YAME "(SOSIZU: 12.63 (6 2-4.8 Hz, YAN), 3.16 (b, 12: 4 .8 Gy, 4H), 3.58 (5, 2H), 4.27 (t, 4H), 6.56 (y, IN, MH), 6.70 (bg, 1H, MH), 6.82 (4, 31-8.7 Hz, 18), 6.89 (y, 1- 9.0 Gy, 28), 6.96 (ai, )-2.7 and 8.7 Hz, IN), 7.28 (0.12: 2.7 Hz, GNI), 7.30-7.36 (t, ZNU, 7.39 (y, 12 8.7 Ha, 2H) , 7.88 (y, 1 3.3 Go, 1H); 19E NMR (282 MGy, SOSIZ): 2 -168.94;

LC/MS: retention time: 18.12 minutes; purity: 98.4295; MS (mass/charge): 512.95 (MH. 7.3.315 M2A(benzothiophen-3-ylmethyl)-5-fluoro-HyM4- | Similar to the preparation of 144-4(3,4-ethylenedioxyphenyl)-5-fluoro-M2 -(3-(3-hydroxyphenyl)-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, M2-(benzothiophen-3-ylmethyl)-5-fluoro-Yim4-(3- and (K945164) tihydroxyphenyl)- 2,4-pyrimidindiamine (40 mg, 5392) is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenia)-4-pyrimidinamine (50 mg, 0.21 mmol) and benzothiophene-3-1l- methylamine (100 mg, 0.61 mmol). IN NMR (SOCI3): g: 4.82 (4, 71- 6.0 Hz, 2), 6.45 (aa, )- 8.1 Ha, 1) . 39-7.46 (t, 2H), 7.82 (pt, KN, 7.89-7.92 (t, sem 2ChU; 19E YAM (282 MGy, SOSIZ): 0 170.02; RH/MS: retention time: 21.29 minutes; purity: 92.97; MS (mass/charge): 367.03 (MNK). Ge) 7.3.316 5-fluoro-M4-(3-hydroxyphenyl)-M2-(3- Similarly to the addition of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-pyridylmethyl)-2,4-pyrimidinediamine trihydroxyphenyl)-2,4-pyrimyldiamine, 5-fluoro-M4-(3-hydroxyphenyl)-m2-4(3- (2945165) pyridylmethyl)-2,4-pyrimidinediamine (40 mu, 6295) is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-( 3-thihydroxyphenyl)-4-pyrimidinamine (50 mg, 0.21 mmol) and 3-pyridylmethylamine (68 mg, 0.63 mmol). YIN YAM? (SOSIZU: Г1 4.40 (4.163 Hz, is e)

Oh, 5.60 (B, 1H), 6.62-6.70 (t, Z), 7.05 (bg, NI), 7.14 (5, 1-2 8.1 Gu, 1), 7.30 (yes, 125.1 and 7.8 Gy, IN), 7.73 (4.2: 7.5 Gy, 1H), 7.80 (y, 1- 3.3 Hn, 1H), 8.49 (y, 1 4.5 b

Ty, 18), 8.65 (5, 1NU; 19E YAM? (282 MGy, SOSI3U; 2 -169.52; RH/MS: retention time: 9.41 minutes; purity: 99.2595; MS (mass/ charge): 312.01 (MH). h- 7.3.2317 5-fluoro-M4-(3-hydroxyphenyl)-M2-(2- Analogous to the preparation of IM4-(3,4-styrenedioxyphenyl)-5-fluoro-142- (3-pyridylmethyl)-2.4-pyrimidinediamine hydroxyphenia)-2,4-pyrimidinedigmine, 5-fluoro-M4-(3-hydroxyphenyl)-M2-(2- se (K945166) pyridylmethyl)-2,4-pyrimidineliamine (40 mg , 6295) are obtained as a result of the reaction of 2-chloro-5-fluoro-Mma-(3-hydroxyphenyl)-4-pyrimidinamine (50 mg, 0.21 mmol) and 2-

From pyridimethylamine (68 mg, 0.63 mmol). TN NMR (SOSIZ): C 4.73 (4.4-63 Hz, (ge) 2H), 5.85.32: 6.0 Hz, IN, MH), 6.48 4.3- 6.9 Hz, 1H), 6.61 (40, 12: 2.7 and 8.1 Gu, 1H), 6.675, 18), 7.13 (03-8.1 by, IN), 7.21 (44, 3- 5, 1 and 7.5 Go, 1H), 7.49 (a, 1- 7.5 Ga, 1H), 7.69 (id, 7-2: 1.8 and 7.8 Hn, 1H), 7, 85 (4, 72 3.6 Hz, EN), 8.38 (Le, 18), 8.56 (ad, 2- 1.2 and 3.9 Hz, 1NU; 1I9K YAM (282 MHz, SOSIZ): s 170.49; LC/MS: retention time: 10.10 minutes; purity: 10095; MS (mass/charge): 312.08 " (pl. 7.3.318 144-(3,5-dimethoxypheni l)-Ch2 -(3- Similar preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- hydroxyphenia)-5-fluoro-2,4- hydroxyphenyl)-2,4-pyrimidinediamine, MA-(3 ,5-dimethoxyphenia)-M24(3-pyrimidinediamine (2926802) hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro- and MA-(3,5-dimethoxyphenyl)-5-fluoro- 4-pyrimidinamine and 3-hydroxyaniline. LC/MS: and - retention time: 18.98 minutes; purity: 9075; MS (mass/mass): 357 (MNE. 7.3.519 4-(3,5-dimethoxyphenyl)- M2-(2- Similar to the preparation of M4-(3,4-eth ylenedioxyphenyl)-5-fluoro-M2-(3-ethoxycarbonylindoyl-7-yl)-5-fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,5-dimethoxyphenyl)-х2-(2 - pyrimidinediamine (K926803) ethoxycarbonylindol-7-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidinamine and 2- ( ee) ethoxycarbonyl-7-aminoindole. LC/MS: retention time: 24.21 minutes; purity: 9195; MS (mass/charge): 452 (Mn. co 7.3.320 M2-43,4-dimethoxyphenyl)-M4-(4- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- ethoxyphenyl)-5-fluoro-2,8-hydroxyphenium)-2,4-pyrimidinediamine, M2-(3,4-dimethoxyphenyl)-M4-(4-ethoxyphenia)- shk pyrimidinedismin (2926108) 5-fluoro-2,4 -pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidinamine and 3,4-dimethoxyaniline. IN YAMRISOSIZ): (Se) (42) ko 60 b5

2 7.89 (a, 1H, 3-3 Hn), 7.45 (ra, 2H, 3-9 7), 7.202, 1H, 2-2.4 Gy), 6.96-6.77 (t . 1, ЗН, 1-7.2 Hz); 19E NMR (SOSIZ): -47473. 7.3.321 M4-4-ethoxyphenyl)-M2-(3- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- tihydroxyphenyl)-5-fluoro-2,4-hydroxyphenia)- 2,4-pyrimidinediamine, M4-(4-ethoxyphenyl)-M2-(3-hydroxyphenyl)-5-pyrimidinediamine (4926146) fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(4-ethoxyphenyl) -5-fluoro-4-pyrimidinamine and 3-hydroxyaniline. 1H NMR (SPZOI): Gy 7.79 (a, 1H, 1-5 402 Hu, 7.54 (09, 2H, 3 2.4 and 7.2 Gy), 7.05-6.97 (t, C), 6.87 (44, 2H, 1-2.4 and 4.2 Hz), 6.41 (t, 1H), 4.02 (d, 2H, I-: 6.6 Hz), 1 ,38 (b ZN, 7: 6.9 Hz); 19E YMe (SrZOB)U; -47444, RH/MS: retention time: 21.15 minutes; purity: 9825; MS (mass/charge): 341 (MN ). 7.3.322 M4-(4-ethoxyphenyl)-m2-(3,4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- 7170 ethylenedioxyphenyl)-5-fluoro-2 ,4-hydroxyphenyl)-2,4-pyrimidinediamine, M«A-(4-ethoxyphenyl)-M2-(3,4-pyrimidinediamine (926213) ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of reaction 2 - chloro-Ma4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidinamine and 3,4-ethylenedioxyaniline.

NMR (SOSIS): 117.87 (8, 1H, 1 31), 7.47 (ai, NI, 1-24 and 5.4 Hz), 7.184, 1H, - 2.4 Go), 6.91-6, 85 (t, ZH), 6.79-6.73 (ta, 2H), 6.64 (b5, 1), 4.25 (b5, AN), 4.05 (4, 2H, 1-65 Hz ) 1.43 (B ЗН, 1-7.2 Hz); 192 NMR (SOSIzu: -47467; RF/MS: retention time: 24.32 minutes; purity: 905; MS (mass/charge)y: 383 (MH). 7.3.323 Ma-(3,4-dimethoxyphenyl)- M2-(4- Analogous to the preparation of 144-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-ethoxyphenyl)-5-fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3 ,4-vimethoxyphenyl)-M2-(4-ethoxyphenyl)-pyrimidinediamine (K926145) 5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(34-dimethoxyphenyl)-5-fluoro-4-pyrimidinediamine and 4-ethoxyaniline. IN NMR (SOSIS): 7.90 (65, 180, 7.37 (99, 2H, 1: 2.4 and 6.3 Hz), 7.21 (y, 1H, 2- 2 ,4 Gy), 7.93 (40, 1H, 1-2 2.4 and 8.1 Hp), b.86-6.80 (t, 4NI), 6.65 (vv, IN), 4, 00 (4, 7H, ex 7.2 0), 3.89 (5,

ZNU, 3.75 (5, ZN), 1.39 (and, ZN, 2: 6.9 Hz); 192 NMR (SOSIZ): -47501; LC/MS: retention time: 22.69 minutes; purity: 9575; MS (mass/charge): 385 (MN). 7.3.324 M4A43,4-dimethoxyphenyl)-5-fluoro-M2-(3- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine hydroxyphenyl) -2,4-pyrimidinediamine, IM44(3,4-dimethoxyphenyl)-5-fluoro-M2-(3- (8926147) hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4 -dimethoxyphenyl)-2-fluoro-4-pyrimidinamine and 3-hydroxyaniline. TN NMR (SOZO0Y 7.774, 1H, 23.3 Hz), 7.15 (0, IN, 12 2.4 Gm), 7.05 (00, TN, 3-5 2.4 and 8.4 Gy), 7.00-6.90 (t, 4H), 6.80 (4, 1H, 7-8.1 Hz), 6.40 (t, IN), 4.05 (a, 2H), 3.80 (5,

ЗН), 3.75 (5, ZNO), 1.29 (6 ZNU; 19E YAM (SPZOB): -47223; RH/MS: duration of Ha! retention: 17.94 minutes; purity: 9995; MS (mass/charge) : 357 (МН. - 5 6« 6 - С Я «Я С 6 "( ( Я ЯЙ Н- -- pre o 7.3.325 M2-(3,4-dimethoxyfecyl)-5-fluoro-M4-(3- Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-tihydroxyphenyl)-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, M2-(3,4-dimethoxyphenyl)-5- fluoro-M4-(3- (8926113) hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-

Mm4-(3-hydroxyphenyl)-4-pyrimidinamine and 3,4-dimethoxyaniline. IN NMR (SOSISU; sl 7.90 (d, IN, 1-6.6 Hz), 7.59 (05, IN), 7.30 (5, 1), 7.20-7.10 (t, 2), 7.00-6.75 (t, (Te) 4H), 6.59 (B4, IN, 1-7.8 Hz), 3.87 (5, ZN), 3.84 (5, ZNU; 192 NMR (SOSISU: -47229; from LC/MS: retention time: 17.77 minutes; purity: 7875; MS (mass/charge): 357 (pl. (e) 7.3.326 M2-(4-ethoxycarbonylmethyleneoxyphenyl )- | Analogous to the preparation of 44-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-5-fluoro-M4-(3-hydroxyphenyl)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, ISHM2 -(4-ethoxycarbonylmethyleneoxyphenyl)-5-h pyrimidinediamine (5926395) fluoro-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4 -pyrimidinamine and ethyl-4-sem aminophenoxyacetate. 1H NMR (CO3O2): IL 7.90 (a, 1, 1-51 Hz), 7.35 (44, 2H,3- 2.1 and 7.2 c), 7 1З(BI1Н, - 7.2 Hz), 7.109, TAN, 7- 6.6 Hz), 6.96 (40, 2Н, 1: 2.4 and so 7.2 Hz), 6.67 (t , 1H), 4.72 (5, 2NU, 4.25 (4.2H, 15: 7.2 Hz), 1.29 (1, ZN, 3- 7.2 Gyu; 192

NMR (SOZOYUU; -21885; LC/MS: retention time: 20.18 min; purity: 9295; MS (mass/charge: 399 (MNK). 7.3.327 5-bromo-M2-(4- Analogous to the preparation of M4- (3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-stoxycarbonylmethyleneoxyphenyl)-MA-(3- | hydroxyphenyl)-2,4-pyrimidinediamine, 5-bromo-M24(4- « hydroxyphenyl)-2,4 -pyrimidinediamic ethoxycarbonylmethyleneoxyphenyl)-Mm4-(3-tihydroxyphenyl)-7,4-pyrimidinediamine (K926396) is obtained as a result of the reaction of 2-chloro-M4-(3-hydroxyphenyl)-4-pyrimylamine and ethyl-4-aminophenoxyacetate.. РХ/ MS: retention time: 21.64 minutes; - s purity: 9295; MS (mass/charge): 459 (MAN). 7.3.328 M2-(4-ethoxyphenyl)-M4-(3,4-) Similar to the preparation of M4- (3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- x z» stylenedioxyphenyl)-5-fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(4-stoxyphenyl)-M4- 4(3,4-" pyrimidinediamine (KU26211) ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4 -ethoxyaniline. IN

NMR(SOSIS): C 7.88 (5, 1H), 7.40 (Bd, 2H, 2-8.7 Gy), 7.27 (ra, 2H, 1-63 Hz), 6.95 (44 , 1Н, 7- З and 9 Hz), 6.856-6.77 (t, ЗН), 6.58 (5, 180), 4.28 (65, 4Н), 2.01 (9, 2Н, 1- 6.9 Hz), 1.40 (, ЗН, 1- 6.9 Hz); LC/MS: retention time: 24.46 minutes; (og) purity: 9095; MS (mass/charge): 383 (MIC). km 7.3.329 2-(3,4-dimethoxyphenyl)-M4-(3,4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- ethylenedioxyphenyl)-5-fluoro-2 . and chloro-M4-(3 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimilinamine x 3,4-(Ce) (42) x 60 b5 dimethoxyaniline. ВХ/МС: duration of retention: 20.98 minutes; purity: 7495; MC (mass/charge): 399 (MN). 7.3.330 M2-(3-chloro-4-fluorophenyl)-M4A-(3,4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- styrenedioxyphenyl)-5-fluoro- 2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(3-chloro-4-fluorophenyl)-M4-(3,4-pyrimidinethiamine (9260218) stylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained in as a result of the reaction 2-

Chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3-chloro-4-fluoroaniline. IN NMR (SOSO): О 7.75 (84, IN), 7.70 (64, 1NU, 7.18 (t, 18), 7.10 (t, 1H), 6.90 (t, 2H) , 6.75 (pi, 1NI), 4.20 (bv, 4H); LC/MS: retention time: 25.04 minutes; purity: 9995; MS (mass/charge): 392 (MIN'YU). 7.3 .331 M2-(4-tert-butylphenia)-MaA-(3,4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-ethylenedioxyphenyl)-5-fluoro-2,4 - hydroxyphenyl)-2,4-pyrimidinediamine, M2-(4-tert-butylphenia)-Mm4-(3,4-pyrimidinediamine (К926219) styrenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction 2-706 chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4-tert-butylaniline 1H NMR(SOSIZU: 2 7.854, 1H, 7-5 3.6 Hz), 7.54 (Ba , 2H, 2-63 Hz), 7.35-7.31 (t, 31), 6.93 (grandfather, IN, 7- 2.7 and 8.7 Hz), 6.83 (a, IN, 7-9 Rc), 6.80 (b5, 1H), 4.23 (5, 4H), 1.28 (c, ZN); LC/MS: retention time: 27.67 minutes; purity: 9809; MS (mass/charge): 395 (MNK), 7.3.332 M4-(3,d-ethylenedioxyphenyl)-M2-(4- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-m2-(3- fluorophenyl)-5-fluoro -2,4-pyrimidinediamine | hydroxyphenyl)-2,4-pyrimidinediamine, IM4-(3,4-ethylenedioxyphenyl)-M2-(4-(K926220) fluorophenyl)-5-fluoro-2,4-pyrimidinediamine are obtained as a result of the reaction of 2-chloro-

M4-(3 d-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4-fluoroaniline. IN NMR (SOS: 21 7.92 (Bv, 18), 7.80 (65, IN), 7.60 (d, 2H)), 6.90 (t, 2H), 6.80 (b5, IN ), 6.65 (B5, 1H), 4.25 (5, 4H); РЧ/МС: duration of retention; 22.87 minutes; purity: 9795; MS (mass/charge): 357 (MNNU. 7.3.333 M44(3,4-styrenedioxyphenyl)-M2-(3- Analogous to the preparation of M4-4(3,4-ethylenedioxyphenyl)-5-fluoro-M24(3" fluorophenyl )-5-fluoro-2,4-pyrimidinediamine ) hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-ethylenedioxyphenyl)-M2-(3- (K926221) fluorophenyl)-5-fluoro-2,4- pyrimidinediamine is obtained as a result of the reaction of 2-chloro-

M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3-fluoroaniline. !H NMR (SOSIS): 0 7.76 (0, 1, 1- 5.6 Cy), 7.39 (p, 2H), 7.14 (y, IN, )- 2.4 Gy), 6.94 -6.85 (ta, ЗН), 6.75 (y, 1Н, 1: 9 Гп), 4.21 (5, 4Н)); ВХ/МС: duration of retention: 27.60 minutes; purity: 10005; MS (mass/charge): 357 (MY Kk). 7.3.334 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(2-methoxystil)-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-ethylenedioxypheninp) --5-fluoro-M2-(2- (K926229) methoxyethyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-isoethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 2-methoxyethylamine. INYAMR | o (SOSIZU 7.81 (b5, 1H), 7.33 (4, 1H,, 7- 2.4 Hz), 6.93 (ai, IN, 1- 2.4 Hz and 9 Go), 6.81 (4, 1H, 129 Hz), 6.53 (5, 1H), 4.25 (65. 2H), 3.54 (65, 2), 3.36 (in, ZNU; РХ/MS: duration of retention : 18.01 minutes, purity: 19095; MS (mass/charge): 321 (MNK). 7.3.335 M44(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(3,4- stylenedioxyphenyl)-5-fluoro-M2-(3-(a4-methoxybenzyl)-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(4 - (Che) (8926230). Methoxybenzyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4-methoxybenzylamine. IN

NMR (SOSIZU 0 7.81 (y, IN, 72 2.7 Gy), 7.27 (t, ZN), 6.86 (t, ZNU, 6.52 (5, IN). b» 5.14 (5 , IN), 4.46 (4, 2H, 1-5.4 Gy), 4.24 (5, 4H), 3.78 (5, ЗН); РХ/MS: retention time: 23.06 minutes; purity: 9495; MS (mass/mass): 383 (MH). chi! 7.3.336 M2-(2,2-difluorobenzodioxol-5-yl)-Ma- Similar to the preparation of Ich4-(3,4-ethylenedioxyphenyl)-5 -fluoro-2-(3-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(2,2-difluorobenzodinocool-5-yl)-M4-( 3,4-He pyrimidinediamine (5926386) ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-43,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 2,2- difluoro-5-so aminobenzodioxol. IN NMR (SOSIS): P 9.39 (5, 1H), 9.24 (5, 1H), 8.06 (d, 1H, 1- 5.6 7), 7, 87 (8, IN, 1-18 Hz), 7.27-7.19 (m, ЗН), 7.08 (04, 1Н, 3- 2.4 and 8.7 Hz), 6.804, 1Н,1 - 9), 4.21 (05, 4H); I9E NMR (SOSIZ): -14012 and -46487; LC/MS: retention time: 25.32 min; purity: 10020; MC (mass/charge): 419 (MN). 7.3.337 M2-(2-ethoxycarbonylindol-5-yl)-Ma4- Similar to the preparation of IMa-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- « (3,4-ethylenedioxyphenyl)-5-fluoro -2,4- hydroxyphenyl)-2,4-pyrimidinediamine, M2-(2-ethoxycarbonylindol-5-yl)-M4-(3,4-pyrimidinediamine (К926476) ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine are obtained as a result of the reaction of 2-chloro-M4-(3,4-styrenelioxyphenyl)-5-fluoro-4-pyrimidinamine and 2-stoxycarbonyl-5-s aminoindole. IN NMR (SOSIS): 2 7.84 (0, 1H, 1 5.4 Gy), 7.764, 1H, 3-36 Gy), 7.509, 1H, 3-9 Gy), 7.23-7.15 ( t, ZN), 7.03 (60, EN, 2-8.7 Hz), 6.78 (4, IN, 1-5 8.7 h Hz), 4.38 (4, 2Н, 12 7, 2 Hn), 4.22 (5, 4NU, 1.41 (i, ZN, 7-2 6.9 Gy); RH/MS: duration and t retention: 23.58 min; purity: 10095; MS (mass /charge): 451 (MNK). 7.3.338 Mm2-(4-cyanomethyleneoxyphenyl)-M4-(3,4- | Similar to the preparation of M4-(3,4-ethylenedioxyphenia)-5-fluoro-M2-(3- ethylenedioxyphenyl) )-5-fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(4-cyanomethyleneoxyphenyl)-M4-(3,4-pyrimidinediamine (K926480) ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine obtained as a result of the reaction of 2-oo chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4-cyanomethyleneoxyaniline.IN YAMRISOSIZ C 7.87 (y, 1H, 1- 3.6 Ho), 7.524, IN, 1- 8.7 Hz), 7.38 (5, IN), 7.28 (b, 1H, 1- 2.4 Hz), 6.96-6.86 (tp, ZN), 6.65 (Ba, 18), co 4.73 (5, 2H), 4.29 (tp, 4H); 19E NMR (SOSIZ): -47416; LC/MS: retention time: 20.49 minutes; purity: 10090; MS (mass/charge): 394 (MNK). -y 7.3,339 M24(3-ethoxycarbonylmethyleneoxyphenyl)- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5"fluoro-M2-(3-(Ce) 42) ko 60 b5

Ma-(3,4-ethylenedioxyphenyl)y-5-fluoro-2,4-| hydroxyphenyl)-2,4-pyrimidinediamine, M2-(3-ethoxycarbonylmethidenoxyphenyl)-MA» pyrimidinediamine (2926482) (3,4-styrenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4- (3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and ethyl-3-aminophenoxyacetate, IN NMR (SOSIS): С 10.53 (5, 18), 8.18 (5, IN), 7.674, 1Н ,

And 4.8 Hn), 7.19-7.07 (t, 5H), 6.86 (4, IN, 9), 6.71 (49, IN, 2 1.8 and 9 Gy), 4, 51 (5, 2H), 4.25 (t, 6H), 1.29 (h, ЗН, 7-7.5 Gy); 9E NMR (SOSIZ); -45640; LC/MS: retention time: 22.71 minutes; purity: 9995; MS (mass/charge); 441 (MIN). 7.3.340 M2-(3-ethoxycarbonylpheny). M4-(3,4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- styrene dioxypheny)-5-fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2- (3-stoxycarbonylphenyl)-M4-(3,4-pyrimidinediamine (KO25745) ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro -4-pyrimidinamine and 3-ethoxycarbonylaniline-. IN NMR (SOSIZ); 2 8.04 (5, 1), 7.94 (05, 1NU, 7.90 (Ba, 1H), 7.68 (Ba, 1.3: 7.5 Hz), 7.35 (5 1, 5 8 Sv), 7.28 (4, 1H, 125 2.4 Hz), 7.07 (5, 1H), 6.93 (49, 1H, 1 V and 8.7 Hz), 6.83 ( y, IN, 1-9 Gy), 6.64 (B, 1H)), 4.35 (4, ЗН, 1- 7.2 и), 4.26 95, ЗН), 1.35 (и, ZN, 1-7.5 Gy); 19KE NMR "(SOSIZ): -47247; LC/MS: retention time: 15.88 minutes; purity: 10095; MC (mass/charge): 41 I (MN). 73.34 Mm443,4-styrenedioxyphenyl)-5-fluoro-M2- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(2-tihydroxystil)-2,4-pyrimidinediamine hydroxyphenyl)-7 . stylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 2-hydroxyethylamine, IN YAM (СО300): (27.7 (65, 1), 7.32 (y, 1Н,1- 2,4 Gy), 7.05 (44, TN, 1: 2.4 and 9 Gib), 6.75 "I 1H, 2-89 Hyd), 4.21 (5, AN), 3.67 (0 2H, 12 5.7 Hz) , 3.38 (6 2H, 7: 5.4 Hz); 192

NMR (SOZOB): 448518; PSMO; retention duration: 15.54 minutes; purity: 10095; MC (mass/charge) in: 307 (MN). 7.3.342 M24(4-ethoxycarbonylmethyleneoxyphenyl)- | Similar to the preparation of M4-43,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-ma-(3,4-styrenedioxyphenyl)-5-fluoro-2,4- | hydroxyphenyl)-2,4-pyrimidinediamine, M2- (4-ethoxycarbonylmethyleneoxyphenyl-M4-pyrimidinediamine (K925747) (3 d-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidineliamine is obtained as a result of the reaction of 2-chloro-M4-4(3,4-ethylenedioxyphenyl)-5-fluoro- 4-pyrimidinamine and ethyl-4-aminophenoxyacetate. 1H NMR (SOSIS): H1 7.88 (5, 1H), 7.42 (494, 7H, 1- 2.4 and 6.9

Hz), 7.28 (9, IN, /- 3 Gi), 6.95-6.81 (to, 4NI), 6.59 (5, 1), 4.59 (z, 48), 4, 28 (4, 2H, I 5.2 Hz), 1.30 (5, ЗН, 7- 6.1 Hz); 192 NMR (SOSIZ); -47570; LC/MS: retention time: 22.74 minutes; purity: 10095; MS (mass/charge): 441 (MIN). 7.3.343 142-4(33-chloro-4-hydroxy-5-methylphenyl)-5- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-fluoro-im4-(3-hydroxyphenyl)-2,4-hydroxyphenia)-2,4-pyrimidinediamine, 142-(3-chloro -4-hydroxy-5-methylphenyl)-5- z. Pyrimidinediamine (K940233) fluoro-Ma43-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-o-chloro-5-fluoro-Ma4-(3-hydroxyphenyl)-4-pyrimidinamine and 3-chloro-4-hydroxy-5 - methylaniline. LC/MS: retention time: 19.20 minutes; purity: 9495; MS (mass/mass): 360 (M); IN NMR (SOSIZU: 17.93 PN, a, 3-31 c), 7.54 (IN, 8, 12 2.6 g), 730 NN, 1221 g), 721 (NT, 3- 7.9 Hz ), 7.02 (ZN, t), 6.78 (IN, 5), 6.61 an, aa, 7.9 Hz, 3: 21 Hz), 2.26 (ZB. 5). (Te) 7.3.344 1444(3-chloro-4-hydroxy-5-methylphenyl)-5- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-h2-(3-fluoro-M2-(3-hydroxyphenyl)-2,4-hydroxyphenyl)-2,4-pyrimidineliamine, M4-(3-chloro -4-hydroxy-5-methylphenyl)-5-(e") pyrimidinediamine (K940235U fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-Ma4-(3 -chloro-4-hydroxy-5-methylphenyl)-4-pyrimidinamine and 3-h-hydroxyaniline.LC/MS: retention time: 18.20 minutes; purity: 9495; MS (mass/charge): 360 (M); IN NMR (0M5O-α6): 729.26 (IN, 5), 9.23 (1H, 5), 9.16 (1H, 5), 8.89 (1H, 5), 8.14 (IN, 4, 7- 4.5 Gy), 7.66 (1H, d, 22 2.1 Hz), 7.60 1H, 4, 1-21 and.

Gu 7.29 DN, a, 2-8.4 Hn), 7.11 (IN, 8), 706, 5 1-84 Gy), 6.41 OH, y, 1-84

Gi), 2.30 (ZN, 8). c 7.3.345 1424(3,4-dimethoxyphenyl)-5-fluoro-M4-(4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-

I3-(m-morpholinyl)propyl|oxyphenyl|- hydroxyphenyl)-2,4-lyrimidinediamine, M2-(3,4-dimethoxyphenyl)-5-fluoro-Ma-(4-13-(M-2,A-pyrimidinediamine) (K940250) morpholinyl)propyl|oxyphenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(4-I3-(M-morpholinyl)propyl|oxyphenyl-4-pyrimidinamine and 3,4 -dimethoxyaniline. LC/MS: retention time retention time: 14.72 minutes, purity: 9495; MS (mass/charge); 484 (MH); IN NMR (SOCI3): 77.89 (IN, y, Te: 3.3 Go), 7.47 (2H, 49, 7-9 Hz), 7.22 (1H, a, 1 2.2 Hz), 6.93- shsh 6.76 (5, t), 6 .62 (1H, 9, 4- 2.2 Gy), 4.01 (2, 5, 7: 5.6 Hz), 3.86 (ZY, 5), 3.72 (ZH, 5), s 3.71 (AN, t), 2.58-2.44 (6H, t), 1.97 (2H, t). p z» 7.3.346 M2-(3-chloro-d-hydroxy-5- methylphenyl)-5- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyal)-5-fluoro-M2-(3- and fluoro- sh4-14-13-(M-hydroxyphenyl)-2,4-pyrimidinediamine, M2- (2-chloro-4-hydroxy-5-methylphenyl)-5-morpholinyl)propyl|oxyphenyl-2,4-fluoro-Ma-14-(3-(M-morpholinyl)propyl|oxyphenyl-2,4-pyrimidinediamine is obtained p irimidinediamine (KO40251) as a result of the reaction of 2-chloro-5-fluoro-M4-14-I3-(M-morpholinyl)propyl|oxyphenyl|-4-pyrimidinamine and 2-chloro-4-hydroxy-5-methylaniline. LC/MS: duration. retention: 15.19 minutes; purity: 9499; MC (mass/weight): 488 (MN); IN NMR (og) (SOS) o Won, a, 1-33 Hz), 7.52 (1, a, I 2.5 Hn), 7.44 (2H, y, 8.7 Gy), 6, 97

H, a, 7- 2.5 Gy), 6.91 (2H, y, 9 Gy), 6.71 (IN, 5), 6.66 (IN, 2.5 Gy), 4.03 (2H , I ko 6.03 Gy), 3.74 (4H, 1, 7- 4.65 Hz, 2.60-2.43 (68, t), 2.23 (ZN, 8), 1.49 ( 2H, t). 7.3.347 Ma-(3,5-dimethyl-4-hydroxyphenia)-M2-(3- | Similar to the preparation of 4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- -- ethoxycarbonylmethyleneoxyphenyl)-5-hydroxyphenyl)-2,4-pyrimidinediamine, M4-4(3,5-dimethyl-4-hydroxyphenyl)-M2-(3-fluoro-2,4-pyrimidinediamine (KU40253) ethoxycarbonylmethyleneoxyphenia)-5 -fluoro-2,4-pyrimidinediamine is obtained in (Ce) (42)

F) ko 60 b5 as a result of the reaction of 2-chloro-M4-(3,5-limethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidinamine and ethyl-3-aminophenoxyacetate. LC/MS: retention time: 21.79 minutes; purity: 91 95; MO (mass/charge): 427 (MN; IN YAM (0M50-y6): PT 9.80 (IN, 5), 8.30 PN, 5), 8.23 (1Н,, 4, 22 4.5 Gi), 7.37-7.17 (5H, pt), 6.66 (IN, 4, 159

Ty), 4.73 (OH, 5), 4.25 (ZN, in, 2: 7.2 Hz), 2.23 (BN, 5), 1.29 (ZN, 6 3- 7.0 Go ). 9 7.3.348 M2-(3-tert-butylphenia)-M4-(3- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-hydroxyphenyl)-2 ,4-pyrimidinediamine, M2-(3-tert-butylphenyl)-M4-(3-fluoro-4-pyrimidinediamine (59402661 ethoxycarboniamethyleneoxyphenyl)-5-fluoro-4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3- ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-tyrimidine and 3-tert-butylaniline, LC/MS: retention time: 28.17 minutes; purity: 96 25; MS (mass/charge): 439 (Mn), 440 (MNH) ; IN NMR (OM5O0- abu c 9401Н, 5), 9.19 (1Н, 5), 8.21 (IN, 8, 1- 3.6 Hz), 7.781 Н, 8, 1- 8.5 Gy) 7.60 70 (IN, tu, 7.48 (1N. 621-2 Gy), 73 1, 6, 2- 8.5 Gy), 7.25 (IN, 6 1-e 8.5 Gy), 7.02 01 H, d, 18.5 Hn), 6.70 (IN, 44, 1» 8.5 and 2 Hz), 4.79 (2H, 5), 4.26 (2H, 4, 7 -- 7.2 Hz), 1.33 (9H, 5), 1.29 (ZN, I, 12 7.2 Gy). 7.3.349 5-fluoro-М4-4(3-isopropylphenyl)-М2х2- Similar to the preparation of М4-(3,4-ethylenedioxyphenip)-5-fluoro-М2-(3-methoxycarbonylbenzofur-5-1l)-2,4- hydroxyphenyl)-2,4-pyrimidinediamine, the sum of 5-fluoro-M4-(3-isopropylphenyl M2-4(2-pyrimidinediamine and 5-fluoro-M24(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine and 5 -fluoro-M2-(2-ethoxycarbonylbenzofur-5-1ya)- M4 -(3-ethoxycarbonylbenzofur-5-yl)- MA -(3-isopropylphenyl)-2,4-pyrimidinediamic isopropylphenyl)-2,4-pyrimidinediamine is obtained in as a result of the reaction of 2-chloro-5-fluoro-M4-(3-isopropylphenyl)-4-

Co40284 of pyrimidine and ethyl-3-aminophenoxyacetate. (-АСО2Ме).. РХ/MS: retention time: 25.41 minutes; purity: 50.61 de; MS (mass/charge: 411 (MNK;

YAMRIUM5O-y6): PI 9.381, 5), 9.29 PN, 5), 8.20 (IN, 4, 1- 3.9 Gy), 7.85 (IN, 4, 1- 93 Hn) 758 ( 1H, 1-16 Hu, 7.43-7.33 (ZH, t), 7.18 (1H, 6.2-8.2 Ho), 7.05 (IN, a, 1-78 Gy), 6 ... ,26 (6Н, 4, 12: 7.2 Hz) (Е-СО2EO) LC/MS: retention time: 26.99 minutes; purity: 39 32; MS (mass/charge): 425 (MNK); IN NMR (OM50O-4abu: C 9.38 (1H, 5), 9.29 (1H, 5), 8.20 (1H, 4, 7-2: 3.9 Gy), 7.85 (IN, y, 2- 9.3

Gy), 7.58 (IN, 615: 1.6 Gy), 7.43-7.33 (ZH, t), 7.181 H, 6 72: 8.2 Hz), 7.05 1H, a, 1 : 7.8 Gy), 6.53 (1 H, 44, 7-: 8.4 and 2.1 g), 4.71 (OH, 5), 4.25 (2H, d, /7- 7 ,2 Gy), 2.95 IN, quintuplex, 12: 7.2 Hz), 1.31 (ZN, 0 1-7.2 Gy), 1.26 (6H, y, 1 7.2 Go). 7.3.350 Ma443-tert-butylphenyl)-5-fluoro-HM2-(2- Analogously to the preparation of 1M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-methoxycarbonylbenzofur-5-yl)-2,4 - hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3-tert-butylphenia)-5-fluoro-M24(2-pyrimidinediamine K940281 methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-( 3Z-tert-butylphenyl)-2-chloro-5-fluoro-4-pyrimidinamine and 2-methoxycarbonyl-z-aminobenzofuran. LC/MS: retention time: 26.76 g) minutes; purity: 97 95; MC (mass/charge): 435 (MN); IN NMR (0M50-46); P 9.41 (2H. 8I), 8.27 (IN, 5), 8.21 IN, 4.7 3.9 Gi), 7.98 (IN, tu, 7.77-7.60 (ZN , t), 7.37 (IN,

UVA), 7.22 (1Н, а, 78.1 Gy), 3.98 (ЗН, 5), 1.34 (9Н, 5). 7.3.351 5-fluoro-M4-(3-isopropylphenyl)-M2-(2- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-Fluoro-M2-(3- (Te methoxycarbonylbenzofur-5-yn)- 2,4- hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-M4-(3-isopropylphenyl)-M2-(2-pyrimidinediamine K940283 methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinedismine is obtained as a result of the reaction of 2- chloro-5-fluoro-M4-(3-isopropylphenyl)-4-pyrimidinamine and 2-(o)methoxycarbonyl-5-aminobenzofuran. LC/MS; retention time: 20.05 minutes; purity: 99 0; MS (mass/ charge): 420 (Mk), 422 (MN; 1H NMR (OM5O0- chi! 46): 1100018, 5), 9.95 (1H, 5), 8.31 IN, 8, 14.8 P), 8 ... 5), 2.83 (IN, with willow, P: 6.9 Hn), 1.20 (6H, y, 7: 6.9 Hz). 7.3.352 M2-P1,1xdihydroisobenzofuran-Igon-6b- Similar to the preparation of Me-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-soyl)-M44(3,4-ethylenedioxyphenyl)-5-fluoro - hydroxyphenyl)-2,4-pyrimidinedismine, M2-(1,1-lihydroisobenzofuran-gon-6-yl)-MA-2,A-pyrimidinediamine (K926786) (3,4-ethylenedioxyphenyl)-5-fluoro-2, 4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and the compound 6-amino-1,1-digylroisobenzofuran-I-one. EN NMR (0M50-46): GP 10.29 (5, 1H), 9.85 (5.1), 8.224, 1H, 7: 4.8 Hz), 8.20 (d, IN, 75 1, 2 Hz), 7.86 (4d, IN, 1- 2.4 and 8.7 Gy), 7.54 (4, 1H, 1-84 Hn), 7.22 (0, 1H, 72: 2.4 Hz ), 7.13 (40, IN, 1- 2.1 and 9 Hz), 6.81 (4, "

IN, 158.7 Gy), 5.34 (in, 2NI), 4.20 (5, 4NU; PH/MS: retention time: 17.40 minutes; purity: 8395; MS (mass/charge): 395 ( МНК). -5-fluoro-7,4- hydroxyphenyl)-2,4-pyrimidinediamine, M2-Y3-(3-apetamidphenoxy)ipropyl-h4-(3,4-p pyrimidinediamine (K926787) ethylenedioxyphenyl)-5-fluoro-2, 4-pyrimidinediamine is obtained as a result of the reaction of 2-n» chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3-M-acetamidophenoxy-3-propylamine. IN NMR (DM 50-46): 310.45 (b5, 18), 10.07 (5,

IN), 8.42 (5, 1NU, 8.20 (5, 1NU, 7.37 (y, 1Н, 2-3 Hz), 7.31 (5, 1Н), 7.20-7.05 ( t, ZH), 6.83 (0, 1H, I-9G), 6.530, 1H, 7- 6.6 Gy), 4.18 (5, 4H), 3.95 (i, 2H, 1-6 Hz) . purity: 9995; MS (mass/charge): 454 (MH), 7.3.354 M2-14-4,5-dichloro-IN-imidazole-1- Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro -M2-(3-coyl)phenyl-M4-(3,4-styrenedioxyphenyl)-5- and hydroxypheny)-2,4-pyrimidinediamine, M2-(4-(4,5-dichloro- I H-imidazole- Il l)phenia|- fluoro-2,4-pyrimidinediamine (926788) M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3, of 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4,5-dichloro-IN-imidazolamine, IN NMR (0М50-46): 17 10.10 (5, 1Н), 9.85 (5, 1Н), 8, 20 (Se) 42) ko 60 b5

(4.1, 2-2 4.2 C), 8.01 (5, 114), 7.78 (4, 1H, 1--8.7 Gy), 7.36 (a, IN, 4- 59 Hz), 7.25 (4, 1H, I-3 g), 7.14 (89, 1H, 1-2 21 and 9 Hz), 6.85 (4, 1H, 72: 8.7 Go) ; LC/MS: retention time: 23.59 minutes; purity: 9595; MC (mass/charge): 474 (MN). 7.3.355 M2-(2,4-dimethoxyphenyl)-Ma4-(3,4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-ethylenedioxyphenyl)-5-fluoro-2, 4-tihydroxyphenyl)-2,4-pyrimidinediamine, IM2-(2,4-dimethoxyphenyl)-M4-(3,4-pyrimidinediamine (KU26789) ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2- chloro-M4-4(3,4-styrenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 2,4-dimethoxyaniline. IN NMR (0M50-46): P 10.35 (5, IN), 8.14 (64, 18), 7.38 (4, 1H, 1-9 Gy), 7.23 (5, 1H)) , 7.094, 1H, 32-8.7 Go), 6.794, 1H, 7- 8.7 Hn), 6.66 (6, 1H, 3 2.4 Hz), 6.49 (08, IN, 7 2.4 and 9 Hyd), 4.22 (5, 4H), 3.77 (5, 6NU; PH/MS: retention time: 20.93 minutes; purity: 9505; MS (mass/charge): 399 ( МН) 7-3.356 M4-3,4-ethylenedioxyphenyl)-5-fluoro-MO- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(2-isopropylphenyl)-2,4-pyrimidinediamine | hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-ethylenedioxyphenyl )-5-fluoro-M2-(4- (8926790) isopropylphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-Ma-(3,4-styrenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4- isopropylaniline. YIN YAM? (orMm80-ав6): 10.30 (5, IN), 10.50 (5, 18), 8.224, 1Н, 12 5.4 Hz). 7.37 (8, IN, 12 8.4 Hz), 7.26 (а, EN, 12 З Hz), 7.18 (z, 1Н), 7.15 (8, 1Н), 7.06 ( dd, IN, /- 3.3 and 8.7

Hz), 6.81 (y, 1H, Re 8.7 Hn), 4.23 (5, 4H), 2.85 (septet., 1H, 22 7.2 Gy), 1.17 (y, 6H, I - 6.9 Gy); LC/MS: retention time: 24.91 minutes; purity: 9575; MC (mass/charge): 381 (MN). 7.3.357 M243,5-dimethoxyphenyl)-M4-(3,4- Analogous to the preparation of Ma4-(3 4-ethylenedioxyphenyl)-5-fluoro-M2-(3- ethylenedioxyphenyl)-5-fluoro-2,4- hydroxyphenyl )-2,4-pyrimidinediamine, I42-(3,5-dimethoxyphenyl)-h4-(3,4-pyrimidinediamine (926791) ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-Ma4 -(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3,4-dimethoxyaniline. 1 NMR (0M50-46): 0 10.08 (5, IA), 9.99 (v, 1), 8.19 (t, 1H), 7.21 (4.1H, 1-24 Hz), 7.14 (49, 1H, 1-2, and 5.7 Py), 6.798, 1H, 7-9 Hn), 6.72 (5, 1H), 6.20 (4, 1H, 34-18 Gy ), 4.21 (5, 4H); LC/MS: retention time: 21.19 minutes; purity: 9395; MC (mass/charge): 399 (MN). 7-3.358 242,5-dimethyl-4-hydroxyphenyl)-Ma- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-3-fluoro-M2-(3-(3,d-ethypenclyoxyphenyl)-5-fluoro-2 . as a result of the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 2,5-dimethyl-4-hydroxyaniline. IN NMR (SOYUZOR: si 7.699, 1H, 1 359 Hz), 7 16( 1.124

Hz), 7.05 (6, 1H, 22: 2.4 Hz), 7.024, 18, 2 1.2 Gy), 6.66 (5, 1H), 6.63 (8, 145), 6, 62 (5, c 1H), 4.19 (5, 4H)), 2.12 (c, 313), 2.10 (5, ЗН); РЧ/МС: duration of retention; 19.80 o'clock (Se) (2) che s so - . and? so ko -y (Se) 42) ko 60 b5

00025200 20 202 0 0 2 p ronneseyov about MO conviction by SOUND 7.3.359 M44(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(5Z-methyl-3-pheny-4-oxazolyl)-72,4-hydroxyphenyl)-2,4-pyrimidinediamine, M4- (3,4-ethylenedioxyphenyl)-5-fluoro-M24(5-pyrimidinediamine (K926793) methyl-3-phenyl-4-oxazolyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4 -etiphendioxyphenyl)-5-fluoro-4-pyrimidinamine and 5-methyl-3-phenyl-4-oxazopilamine. IN NMR (SOSOI: Gy 7.80-7.55 (t, 2), 7.45 (64, 18), 7.20 (t,

IN), 7.00 (t, 1H), 6.65 (j, 1H), 4.20 (5, 4H), 2.35 (v, ZN); LC/MS: retention time: 20.51 minutes; purity: 7895; MS (mass/charge: 420 (MN). 7.3.360 M4-(3,5-dimethoxyphenyl)-M2-(3- Analogously to the preparation of I44-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3x ethoxycarbonylmethyleneoxyphenyl) )-5-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,5-dimethoxyphenyl)-M2-(3-fluoro-2,4-pyrimidinediamine (К926795) ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-nyrimidinediamine obtained as a result of the reaction of 2-chloro-M4-(3,5-limethoxyphenyl)-5-fluoro-4-pyrimidinamine and ethyl-3-aminophenoxyacetate. LC/MS: retention time: 21.02 minutes; purity: 8425; MS ( mass/charge): 429 (MH), 7.3.361 4-(3,4-ethylenelioxyphenyl)-M2-(3- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- ethoxycarbonylmethyleneoxyphenyl )-5-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-ethylenedioxyphenyl).M2-(3-ethoxycarbonyl-2,4-pyrimidinediamine ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine (K926797) obtained as a result of the reaction of 2-chloro-M4-(3,4-dimethoxyphenyl)-5-ethoxycarbonyl-4-tyrimidineamine and ethyl-3-aminophenoxyacetate. LC/MS: long retention time: 75 27.60 minutes; purity: 8290; MS (mass/charge): 495 (MNK). 7.3-362 Ma-(3-hydroxyphenyl)-M2-(3-) Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-hydroxyphenyl)-2,4-pyrimidinediamine . -(3-hydroxyphenyl)-4. pyrimidineamine and ethyl-3-aminophenoxyacetate. LC/MS: retention time: 24.78 minutes; purity: 8575; MC (mass/charge): 453 (MN). 7.3.363 5-fluoro-M4-(3-hydroxyphenyl)-M2-(2- Analogously to preparation IM4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-methoxycarbonylbenzofuran-5-yl)-2, 4-tihydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-M4-(3-hydroxyphenyl)-M2-(2-pyrimidinediamine (К926614) methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine are obtained as a result of the reaction of 2- chloro-3-fluoro-M4-(3-hydroxyphenyl)-4-nyrimidineamine and 2-methoxycarbonip-5-aminobenzofuran. IN NMR (SOZOB): 01 9.47 (5, 1H), 9.33 (5, 1H)), 9.23 (5, IN), 8.26 (8, 15), 8.09 (y, IN, 7" 3.6 Gy), 7.59 (t, ZN), 7.13 (l, ZNU), 6.53 (y, IN, 1-7.5 Hz), 3.87 (z, ZN), 3.87 (in, ZN). sem 7.3.364 M2-(2-ethoxycarbonylindol-5-yl)-5-fluoro- | Similarly to the preparation of IM4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- i o (Ce) (22) че с со

M4-(3-hydroxyphenyl)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(2-ethoxycarbonylindole-5-1l)-5-fluoro-MA4-pyrimidinediamine (2926615) (3-hydroxyphenyl)-2 ,4-Hnrymidylamine is obtained as a result of the reaction of 2-chloro-5-fluoro-m4-(3-hydroxyphenyl)-4-pyrimidinamine and 2-ethoxycarbonyl-5-aminoinlolol. 1H NMR (SOZOV): 7.95 (y, 1H), 7.840, IN, 12 3.9 d), 7.34 (5.18), 7.334 IN, 1-1.8 Hn), 7.22- 71.19 (t, 2H), 7.11-7.05 (t, 2H), 6.55 (t, 1H), 4.62 (v, 2NI), 4.38 (a, « 1H,3 - 6.9 Hz), 1.40 96, ZN, 1- 7.5 Gy). 7.3.365 M2-1444,5-dichloro-1Nimidazole-1. Analogous to the preparation of Ma-(3,4-ethylenelioxyphenyl)-5-fluoro-M2-(3- yl)pheny|-5-fluoro-M4-(3-hydroxyphenyl)-hydroxypheny)-2,4-pyrimidinediamine, M2- 14-(4,5-dichloro-1H-imidazol-1-yl)phenyl|-5-s 2,A-pyrimidinediamine (5926777) fluoro-M4-4(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result reactions of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine and (4,5-dichloro-H-imidazol-1-nyl)-4-aniline. LC/MS: retention time: 22.09 minutes; purity: 9850; MS "p (mass/charge): 431 (MIN). 7.3.366 5-fluoro-M4-(3-tihydroxyphenyl)-M2-(4- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro- M2-(3- isopropylphenyl)-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-Ma-(3-hydroxyphenyl)-M2-(4-(K926778) isopropylphenyl)-2,4-pyrimidinediamine obtained as a result of the reaction of 2-chloro-5- (o e| fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine and 4.isopropylaniline. LC/MS: retention time: 23.08 minutes; purity: 9995; MS ( mass/charge): 439 (MH). ko 7.3.367 5-fluoro Ma4-(3-hydroxyphenyl)-M2-(5- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3 - methyl-4-oxazolyl-2-phenyl)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro M4-(3-hydroxyphenyl)-M2-(5-methia-4-k pyrimidinediamine (5926779 ) oxazolylphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-tihydroxyphenyl)-4-pyrimidinamine and 5-methyl-4-oxazolyl-2-phenyl-1-amine. /MS: retention time: 23.08 minutes; purity: 9995; MS (se) (mass/charge): 439 (MNK). RH/ MS: retention time: 19.17 minutes; purity: 8195; MC (mass/charge): 378 (MN). 1) 7.3.368 M2-(3,5-dimethoxyphenyl)-5-fluoro-Mm4-(3- Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2, 4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, М2-(3,5-dimethoxyphenyl)-5-fluoro-Ма4-(3-(К926780) hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro- 5-fluoro-

M4-(3-hydroxyphenyl)-4-pyrimidinamine and 3,5-dimethoxyaniline. LC/MS: retention time: 19.61 minutes; purity: 975; MC (masv/charge): 357 (MN). 7.3.369 Ma4alre- Similar to the preparation of M443,4-styrenedioxyphenyl)-5-fluoro-M2-(3-

HF) butoxycarbonylmethyleneoxyphenyl)-5-hydroxyphenyl)-2,4-pyrimidinediamine, M4-(4-tert-fluoro-M2-(4-butoxycarbonylmethyleneoxyphenyl)-5-fluoro-IM2-(4-methoxycarbonylmethyleneoxyphenia-2,4- methoxycarbonylmethylethoxyphenyl- 2,4-pyrimidinediamine is obtained as a result of the reaction of pyrimidinediamine (K926572) with M4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidinamine and methyl-4-aminophenoxyacetate. IN NMR (SOSISU: si 7, 49 (4, 2H, 60 b5

Still 1-8.7 Hz), 7.40 (a, 24, 2- 9.3 and), 6.89 (a, 2H, I: 9.3 Hz), 6.85 (y, 2H, 1 -87 g), 4.62 (5, 2H), 4.52 (in, 2H)), 3.81 (5, ZNI), 1.49 (5, 9H); LC/MS: retention time: 24.68 waves; purity: 10095; MC (mass/charge): 499 (MN). 7.3.370 5-fluoro-M4-(3-isopropoxyphenyl)-M2-(2- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-methoxycarbonylbenzofuran-5-1l)-2 . 2-chloro-5-fluoro-M4-(3-isopropoxyphenyl)-4-pyrimidinediamine and 2-methoxycarbonyl-5-aminobenzofuran, IN NMR (SSZ): GP 8.09 (0, 1H, 2-2,4 Gy) . 3 Gy), 7.249 tp, 21), 7.10 (t, 1), 6.97 (be, 1NU, 6.74 (4, 1H, 22: 2.4 Gy), 6.68 (44, 1 , le 2.1 and 6.9 Gy), 4.49 (zero., IN, 12: 5.7 Hz), 3.98 (in, ZN), 1.30 (y, 6НЬ 2: 5.7 Hz); LC/MS: retention time: 25.86 minutes; purity: 9495; MS (mass/mass): 437 (MH). 70 7.3.371 Ma-(a-tert-butylphenyl)-M2-2- Similar preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-ethoxycarbonylindol-5-yl)-5-fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine inu, M4-(4-tert-butylphenyl)-M2-(2-pyrimidinediamine (К926474) ethoxycarbonylindol-5-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction MA-(tert-butylcarbonylmethyleneoxyphenial)-2 -chloro-5-fluoro-4-pyrimidinamine and 2-ethoxycarbonyl-5-aminolindole. 1H NMR (SOSIS): and 8.05 (y,

IN, 12 1.8 Hyd), 7.85 (4, IN, 13.9 Hz), 7.58 (3, 2H, 7" 9 Hyd), 7.36-7.10 (tp, 4NU, 7 ,03 i5, 1), 6.95 (Ba, 18), 6.54 (aa, 1, 3-7.2 Hz), 4.36 (d,2H, 1 7.2 Gy), 1.40 (6 ZN, 1-7.5 Hz), 1.33 (5, UVU; LC/MS: retention time: 28.67 minutes; purity: 10095;

MS "(mass/charge) in: 449 (MNE). 7.3.372 M4-(4-tert-butylphenyl)-5-fluoro-M2-(2- Similar to the preparation of M4-(3,4-ethyleudioxyphenyl)-5-fluoro-M24(3- mexoxycarbonylbenzofuran-5-yl)-2 . M4-(tert-butylcarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro-4-pyrimidinamine and 2-methoxycarbonyl-5-aminobenzofuran. 1H NMR (SOSIZU 0 8.6 (5, IN), 8.09 )4, IN, 72 1.8 Hz), 7.86 (8, IN, 22 3.3 Hz), 7.54-7.36 ( t, 6H), 6.90 (t, 1H) 3.97 (5, ЗН), 1.36 (5, 9H), 197 NMR (SOSIZ3): -47188; LC/MS: retention time: 29.69 minutes; purity: 5479; MS (mass/charge): 393 (M-41). 1.3.373 M2-(3,4-ethylenedioxyphenyl)-M4-(2- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-methoxycarbonylbenzofuran-5-18)-5-tihydroxyphenyl) -2,4-pyrimidinediamine, M2-(3,4-styrenedioxyphenyl)-M4-(2-fluoro-2,4-pyrimidinediamine (К926485) methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine is obtained in as a result of the reaction of 2-chloro-M2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinamine and 2-methoxycarbonyl-5-aminobenzofuran. NO NMR(SOSIS): C 8.07 (5, 1H), 7.76 si (8, 1H), 7.44 (t, З), 7.13 (t, 1H), 6.68 (tp, 2HO , 4.18 (5, 41), 3.95 (5, ZN); LC/MS: no retention time: 26.63 minutes; purity: 10095; MS (mass/charge): 437 (MN). ) 7.3.374 Mma-(3-ethoxycarbonylmethyleneoxyphenyl)- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-42-(3-

M2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4- | hydroxyphenyl)-2,4-pyrimidinediamine, Ma-3-ethoxycarbonylmethyleneoxyphenyl)-142-pyrimidinediamine (926774) (3,4-ethylenedioxyphenyl)-5-fluoro-2,1-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-( 3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinamine and 3,4-ethylenedioxyaniline. 1H NMR (SOSISU: OO 7.92 (0, 1H, 2-36 g), 7.67 (5, (se) 1), 7.40 (5, 1NU, 7.28-7.21 (t, 28), 7.01-6.96 (t, UNII), 6.80 (t, 2H), 6.68 (y, 1H, 1H), 4.61 (5, NU, 4.25 (t, 6H), 1.25 (B, ZN, 1: 6.9 Hz); LC/MS: trivadity Technical retention: 22.03 minutes; purity: 8429; MS (mass/charge: 441 (MN). 7.3. 375 M44(3-ethoxycarbonylmethyleneoxyphenyl)- | Similar to the preparation of 144-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- che 5-fluoro-M2-(3-hydroxyphenyl)-2,4- hydroxyphenyl)- 2,4-tyrimidinediamine, M4-(3-ethoxycarbonylmethyleneoxyphenyl)-5-pyrimidinediamine (K926775) fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2- with chloro-M4-(3-ethoxycarbonylmethyleneoxyphenyl) )-5-fluoro-2,4-pyrimidinamine and 3-hydroxyaniline. LC/MS: retention time: 19.50 minutes; purity: 8490; MS (mass/charge): 399 (MNE). c 7.3.376 M4- (4-aminocarbonylmethyleneoxyphenyl)- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M4-(3-

M2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-| hydroxyphenyl)-7,4-pyrimidinediamine, M4-(4-amipocarbonylmethyleneoxyphenyl)-M2-pyrimidinediamine (K945171) (3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4- (4-azinocarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidinamine and 3,4-ethylenedioxyaniline. IN NMR (acetone-yb): 1 C 424-431 (t, 4H), 4.51 (5, « 2H), 6.77 (4, 2-87 Hn, IN), 6.95 (at, and : 8.7 Gy, 1H), 7.06 (4, 159.3 Hz, 2NU, 7.28 (t,

INU, 7.71 (a, 22 9.0 Go, 2H), 8.15 (t, 1H); LC/MS: 15.23 min, 97.0590; MS in (mass/charge): 412.01 (MNK). c 7.3.377 (8935019): 5-fluoro-M2-(3-hydroxyphenyl)- | Analogous to the preparation of M4-(3,4-ethiyaenedioxyphenyl)-5-fluoro-M2-(3-t Ma-Idi-(4-chlorophenyl)methyl-2,4-tihydroxyphenyl)-4-pyrimidinediamine, 5-fluoro-I42- (3-tihydroxyphenyl)-M4-Hdi-(4- and R.pyrimidinediamine xchlorophenyl)methyl/|-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-aminophenol and M-(2-chloro-5-fluoro-pyrimilinium)- 1, I-d(4-chlorophenyl)methylamine.

LC/MS: retention time: 25.59 minutes; purity: 9195; MS (mass/charge) in: 421 and (MNya-SI). 7.3.378 (8935020); . -9-yl)-5-fluoro-4-pyrimidinamine and 3-aminophenol. IN NMR (SOSIS): HI 7.854, IN, 7- 2.9 Gy), 7.74 (4, 2H, 12 7.6 Gy), 7.54 (d, 2H, 1- 7.6 Gy), 7.41-7.28 (t, -k BNO). 7.14-7.05 (t, 2NI), 6.56 (y, IN, 2-5 8.8 Hz), 5.28 (d, 1H, 7-8.8 Gy); RH/MS: (Se) (42) ko 60 b5

02202212 reno uranana 80 hvadnko chit VUE MIS (svy ZVYAKMNKH 7.3.379 (K935021): (-)-5-fluoro-Ma4-(144- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-Sh2-( 3-fluorophenyl)ethyl)-M2-(3-hydroxyphenyl)-hydroxyphenyl)-4-pyrimidinediamine, ()-5-fluoro-Ma-11-(4-fluorophenyl)ethyl|- M2-(3- 2,4- pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-aminophenol and (4)-M-(2-chloro-5-fluoropyrimidinyl)-1-(4-fluorophenyl)ethylamine. IN NMR (SRSISU O 7.794, 1H, 3-33 Gy), 7.38-7.34 (00, 2H, U 5.2 and 8.5 Gy), 7.14 (B 1H, 1- 4.5 Gy) , 7.09 (6, 1H, ze: 8.5 Hz), 7.03 (y, 1H, 2 8.5 Hz), 6.84 (Be 5, 1H), 6.84-6.78 ( dsd, 1, 7» 0.8, 2.0, and 8.2 Hn), 6.46-6.42 (oda, 1H, E- 0.8; 2.0 ka 8.2 Hz), 5 .26 (overlapping yes, IN, Re 7.1 and 7.9 Hz), 5.18 (4, IN, 127.1 Gnu, .59 (4, ZN, 15 71

Hn); LC/MS: retention time: 21.52 minutes, purity: 9296; MS (mass/charge) in: naz (MNY. 7.3.380 (K935023): ()-5-bromo-MA-Y-(4- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2 -(3-fluorophenyl)ethyl|-M2-(3-hydroxypheny)-|hydroxyphenyl)-4-pyrimidinediamine, (5)-5-bromo-M4-(1-(4-fluorophenyl)ethyl-M2-(3- 2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-aminophenol and (3-5-bromo-2-chloro-M4A-1H1-(4-fluorophenyl)ethyl)|-4-pyrimidineamine. NMR (SOSIZ): 7.97 (5, 18), 7.36-7.31 (t, 20), 7.17 (5, 1Nyu), 7.09-7.01 (t, 4), 6 .82 (and,

IN, 1-22 and 8.2 Hz), 6.46 (b, 1H, 1-2.2 and 8.2 Hz), 5.50 (their a, 1H, 1-7.0), 5.27 ( overlapping yes, 1, 7- 7.1 and 7.9 Hz), 1.58 (4, ZN, 2- 7.0 Gy); LC/MS: retention time: 22.64 minutes; purity: 9499; MS (mass/charge): 404 (MNE) 7.3.381 (8935025): 5-bromo-M2-(3-hydroxyphenyl)- | Similarly to the preparation of M4-(3.4-styrenedioxyphenyl)-3-fluoro-I42-(3-

Ma-(M-methyl-2-carbomethoxypyrrol-4-yl)» | hydroxyphenyl)-4-pyrimidinediamine, 5-bromo-M2-(3-hydroxyphenyl)-M4-(M-methyl-5-2.4-pyrimidinediamine carbomethoxypyrrol-4-yl)-2,4-pyrimidinediamine are obtained as a result of the reaction of 3-aminophenol and 5-bromo-2-chloro-MM-methyl-2-carbomethoxypyrrol-4-yl)-4-pyrimidinamine. IN NMR (SOSOSOSOSOSO): 0 7.92 (5, 1H), 7.58 (a, 1H, 72 50

Gy), 7.094, 1H, 5- 8.5 Gu, 7.04 (4, IN, 2- 8.5 Hz), 6.904, 1H, 72 4.5 Hz), 6.81 (9, 1H, le 1.8 Сy), 6.5 (t, 1), 3.82 (5, ЗН), 3.75 (в, ЗН): РХ/MS: retention time: 19.73 minutes; purity: 9095; MS (mass/charge): 419 (MNY) 7.3.382 (2935029): 4-amipuo-5-bromo-M2-(3- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro -M2-( 3-hydroxyphenyl)-2-pyrimidinamine hydroxyphenyl)-4-pyrimidinediamine, 4-amino-5-bromo-M2-(3-hydroxyphenia)-2-pyrimidinamine are obtained as a result of the reaction of 4-amino-5-bromo-2-chloropyrimiline and Z-aminophenol. 11 NMR (0MI50-46): I110.33 (bg 5, IN), 8.27 (5, IN), 7.14-6.06 (t, 2Н), 7.01 (4, 1Н, 751.7 Hz ), 6.54, 1 N, 15 1.7 Hz and 7.0 Hz). 7.3.383 Kkez5iZa: 5-fluoro-Mma4-(3-hydroxyphenyl)- Reaction between 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine and 5-(4-

M2-144(3-phenyl-1,2.4-oxadiazole-5-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole is carried out under the influence of yl)methyleneoxyphenyl-2,4- microwaves at a temperature of 180 OS for 10-20 minutes at a pressure of 20 bar. In Ge) pyrimidinediamine as a result of concentration and addition of 2M HC form 5-fluoro-Mm4-(3-hydroxyphenyl)-M2-(4-4(3-phenyl-1,2,4-oxadiazol-5-1l)methyleneoxyphenyl)-2 ,4- pyrimidinediamine. IN NMR (0M50-46): 2 10.2) (g 5, 1H), 9.91 (Be 5, 180), 8.18 (4, 1, 32: 5.2 Hn), 8.03-7, 99 (t, 2H), 7.61-7.53 (t, ZA), 7.46 (bg 4, 7H, 1-7.9 Hyd), 7.14-7.01 (t, 5H), 5.54 (arr 4, 1H, 1- 7.96 Hz), 5.55 (5, 2H); LC/MS: duration of re) retention: 24.61 minutes; purity: 10095; MS (mass/charge): 471 (MIN). 7.3.384 8935135: 5-fluoro-M4-44- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-1х2-14-(3-phenyl-1,2,4-Me, isopropoxyphenyl)-M2-14 -(3-phenyl-1,2,4-|oxadiazol-5-yl)methyleneoxyphenyl|-2,4-pyrimilinlismine, 5-fluoro-M4-(4-oxadiazol-5-yl)methyleneoxyphenyl|-2,4- isopropyloxyphenia)-M2-(4-(3-phenyal-1,2,4-oxatazol-5-yl)methyleneoxyphenyl|-2,4- or pyrimidinediamine pyrimidinediamine in the form of small solid flakes is obtained as a result of the reaction of 2-chloro-M4- (4-isopropoxyphenyl)-4-pyrmidinamine and 5-(4-Ha!aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole.IN NMR (0ЮМ50-46): (110.21 (bg 5, 1Н) , 9.93 (bg 5, 1H), 8.17 (d, 1H, 7-2 5.2 Hz), 8.02-7.98 (t, 2H), 7.60-7.49 (t , 5H), 7.42 (arr d, 2H, 15: 7.0 Hz), 7.04 (4, 2H, 12 9.4 Gy), 6.89 (vrr 4, 2H, 1- 9.4 Hu), 5.56 so (8, 2H), 4.58 (septet, 1H, 1: 6.4 Gy), 1.23 (arr 6, EN, 1-5 6.4 Gy); LC/MS : duration of sulfurization: 26.90 minutes; purity: 9795; MS (mass/charge): 513 (MIN-E). 7.3.385 VK935136: M4-(3,4-ethylenedioxyphenyl)-5- | Similar to the preparation of 5-fluoro - M4-(3-hydroxyphenyl)-M2-14-(3-phenyl-1,24 fluoro-M2-(4-(3-phenyl-1,2,4-oxadiazole-5- | oxadiazol-5-yl)methyleneoxyphenyl|-2,4-pyrimidinediamic, M4-(3,4- « yl)methyleneoxyphenyl|-2,4- ethylenedioxyphenyl)-5-fluoro-M2-(4-(3-phenyl-1 ,2,4-oxadiazole-5-pyrimidinediamine yl)methidenoxyphenyl-2,4-pyrimidinediamine in the form of small solid flakes is obtained as a result of the reaction of 2-chloro-M4-(3,4-styrenedioxy)phenyl-4- pyrimidinamine and 5- (4-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole, 1N NMR c (OM50-y6y: I210.18 (be 8, 1H), 9.12 (Be 5, 1H)), 8.14 (d, YIN 4.7 Gm), 8.02-7.97 (t, 2H), 7.65-7.52 (t, ZE), 7.44 (4, 2H, 1- 8.8 Hz ), 7.25-7.23 (ta, 1), 7.15-7.08 (t, 10), ; - 7.034, 2H, 2- 8.8 Gy), 6.81 50, 1H, - 8.8 Gy), 5.56 (in, 2NU, 4.24-4.20 (p, 4H);

РХ/MS.: retention time: 26.90 minutes; purity: 9790; MS (mass/charge): 513 (MNyayu 7.3.386 K935137: 5-fluoro-M44(2- Analogous to the preparation of 5-fluoro-Ma-(3-hydroxyphenyl)M2-(4-(3-fevil-1,2, 4-Methoxycarbonylenzofuran-5-yl)-M2-(4-|oxadiazol-5-yl)methyleneoxyphenyl-2,4-pyrimidinediamine, 5-fluoro-M4-(O2-(se) (3-phenyl-1,2, 4-oxadiazol-5-methoxycarbonylbenzofurav-5-yl)-M2-14-(3-phenyl.1,2,4-oxadiazol-5-yl)methyleneoxyphenyl|-2,4-yl)methyleneoxyphenyl-2,4-pyrimidineliamine are obtained as a result of the reaction of 2-chloro-

Kz pyrimidinediamine 5-M4-(2-methoxycarbonylbenzofuran-5-yl)-4-pyrimidinamine and 5-(4-aminophenoxymethyl)-3-phenyl-1,2-4-oxadiazole. 1H NMR (M 50-46): 110.21 (c 5, 1), 9.79 (Lg 5, IN), 8.194, 1H, 1- 4.7 Hm), 8.09 (Be 5, EN) , 7.994, 2H, p 2.3 and 8.2 - Gy), 7.76-7.67 (t, 2), 7.59-7.52 (t, 4H), 7.44 (4.2 , 1- 8.8 Gy), 7.02(4.2H, 3 8.8

Giyu), 5.55 (in, 28), 3.85 (5, ZN); LC/MS: retention time: 27.61 minutes; (Se) (42) ko 60 b5 shi purity: 9295; MC (mass/charge): 553 (MN). 7.3.387 8935138: 5-fluoro-M2-(3-hydroxyphenyl)- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenia)-M2-14-4(3-phenyl- 1,24"

Ma4-14-(3-phenyl-|,2,4-oxadiazol-3-oxadiazol-5-yl)methnylenoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-M2-(3-yl)methyleneoxyphenyl-2,4 - hydroxyphenyl)-M4-(4-(3-pheny-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl|-2,4- pyrimidinediamine pyrimidinediamine in the form of small solid flakes is obtained as a result of the reaction of 2-chloro-5- fluoro-Ma-I4-(3-phenyl-1,2,4-oxaliazol-z-yl)methyleneoxyphenyl|-4-pyrimidinamic and 3-aminophenol. 1H NMR (0M50-4y6): PI8,12 (y, TN, 1- 4.7 Ha), 8.03-7.99 (t, 2H), 7.694, 2H, 412: 5.5 and 8.8 Hz), 7.61-7.53 (t, ЗН), 7, 06 (4, 2H, 42 9.9 Hp"), 6.98 (t, ZNU, 6.38 (rg 5, 1), 5.58 (5, 2H). РХ/MS: retention time: 24.83 minutes ; purity: 9695; MS (mass/charge): 471 (ME). 7.3.388 8935139: 5-fluoro-M2-(4- Analogous to the preparation of 5-fluoro-Ma-(3-hydroxyphenyl)-M2-14-( 3-phenyl-1,2,4- isopropoxyphenyl)-M4-14-(3-phenyl.!,2,4- | oxadiazol-5-yl)methyleneoxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-M2- (4-70 oxadiazol-5-yl)umethyleneoxyphenyl|-2,4- | isopropoxyphenyl)-M4-14-(3-phenyl-1,2,4-oxaliazole-5 -1l)methyleneoxyphenyl|-2,4- pyrimidinedismine pyrimidinediamine in the form of small solid flakes is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-14-(3-phenyl-1,2,4-oxadiazol-5-ylmethyleneoxyphenyl) -4- tyrimidineamine and 4-isopropoxyaniline. 1H NMR (OM 50-46): "110.21 (re, 18, 9.78 (be 5, 190), 8.13 (0, 1H, 12: 4.7 Hz), 8.02-7, 98 (t, 2H), 7.65-7.53 (t, 5H), 7.34 (d, 2H,1- 7.6 g), 7.07 (y, 2M, 12 93 Go), 6 ... 8 Gy); LC/MS: retention time: 29.64 minutes; purity: 9795; MS (mass/charge): 513 (MIN). 7.3.389 Kk935140: M2-(3 4-ethylenedioxyphenyl)-5- | Similar 5-fluoro-IM4-(3-thiepoxyphenyl).M2-(4-(3-phenyl-1,2,4- fluoro-M4-(4-(3-phenyl-1,2,4-oxadiazole- 5-|oxadiazol-5-yl)methyleneoxyphenyl)-2,4-pyrimidinediamine, M2-(3,4-yl)methyleneoxyphenyl|-2,4- ethidenedioxyphenyl)-5-fluoro-M4-(4-(3-phenyl -1,2,4-oxadiazo-5-pyrimidinediamine yl)methyleneoxyphenyl-2,4-lyrymylinliamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(4-(3-phenyl-1,2,4-oxadiazole) -5-1l)methyleneoxyphenyl|-4-pyrimidinamine and 3,4-ethylenediukeianiline. IN YAM? (0M50-46U: 210.31 (re 5, 1), 9.59 (Be 8, 18), 8.114, 1H, 7-5 4.7 Hz), 8.03-7.99 (t, 2H), 7.68-7.29 (t, 5H), 7.14-7.08 (t, 19), 7.06 (8, 2H, 12: 8.8 Hz), 6.90 (0, 1H, 2- 8.8 Go), 6.76 (0, 1, 1 8.8 Hz), 5.59 (5, 2H), 4.22-4.17 (t, 4H); LC/MS: retention time: 21.35 minutes; purity: 9595; MC (mass/charge): 513 (MN). 7.3.390 K935141: 5-fluoro-M4-(3-hydroxyphenyl)- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-H4-(3-phenyl-I,2,84-

M2-14-(3-methyl-1,2,4-oxadiazol-5-oxadiazol-5-yl)methyleneoxyphenyl-2,4-pyrimidinediamine, 5-fluoro-M4-(3-yl)methyleneoxyphenyl)-2,4 - hydroxyphenyl)-M2-(4443-methyl-1,2 А«oxadiazol-5-yl)methyleneoxyphenyl-2,4- pyrimidinediamine pyrimidinediamine in the form of small solid flakes is obtained as a result of the reaction of 2-chloro-5-fluoro-M4- (3-hydroxyphenyl)-4-pyrimidinamine and 5-(4-tt o (Ce) (22) aminophenoxymethyl)-3-methyl-1,2-4-oxadiazole. IN NMR (PM5O-46): 110.91 (Bg chi! 5, 1), 9.91 (bg 5, 1H), 8.18 (ad, 1H, 3-- 4.7 Gy), 7.43 (4, 2H, 1-5 8.8 Hz), 7.15-7.04 (t,

ZNU, 6.96 (4, ZN, 12 8.8 Hn), 6.58 (arr y, 1H, 1: 7.6 Gy), 5.43 (in, 2H), 2.34 (5, ZNU ; with

LC/MS: retention time: 18.63 minutes; purity: 9525; MS (mass/charge): 409 (MNU. not so 7.3.391 K935142: 5"fluoro-M4A-(4- Analogous to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-14-(3-phenyal- 1,24" isopropoxyphenyl)-M2-(4-(3-methyl-1,2,4- 1l)methyleneoxyphenyl)-7,4-isopropoxyphenyl)-M2-(4443-methyl-1,2,4-oxadiazop-5-yl)methyleneoxyphene lI-2,4-pyrimidinediamine pyrimidinediamine in the form of small solid flakes is obtained as a result of reaction 2 -chloro-M4-(4-isopropoxyphenyl)-4-pyrimidinamine and 5-(4-aminophenoxymethyl)-3-methyl-1,2-4-oxadiazole. 1 NMR (0M5O0-46u; 158.16 (y, 18 ,4- 5.2 Hz), 7.52 (44, 2H, 1- 3.5 Hz and 9.3 Gy), 7.40 (8, 2H, 1- 8.8 Hz), 6.98 ( a, 2H, 1- 8.8 Hz), 6.88 (4, 2H, 1- 9.3 Gy), 5.44 (5, 2H), 4.58 (veri, IN, 3- 5.8 Hyi), 2.34 (in, 8 s ZE, 1.24 (0, BN, 3-: 5.8 Hu); LC/MS: retention time: 24.47 minutes; purity: 9395; MS (mass/ charge): 451 (MH). v! z" 7.3.392 8935143: M4-(3,4-ethylenedioxyphenyl)-5- | Similar to the preparation of 5-fluoro-M4-(3-hydroxyphe nil)-M2-(14-(3-phenyl-1,2,4-" fluoro-M2-I443-methyl-1,2,4-oxadiazole-5- | oxadiazol-5-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3,4-yl)methyleneoxyphenyl!-2,4-ethylenedioxyphenyl)-5-fluoro-M2-(4-(3-methyl-1, 2,4-oxadiazole-5-pyrimidinediamine yl)methyleneoxyphenyl)-2,4-pyrimidinediamine in the form of small solid flakes is obtained as a result of the reaction of 2-chloro-M4-4(3,4-ethylenedioxy)phenyl-4-pyrimidinamine and 54( 4-aminophenoxymethyl)-3-methyl. I,2-4-oxadiazole. IN NMR co (OM50-yv): 179.12 (Be 5, 181), 9.04 (b in, IN), 7.99 (4, IN, 1- 3.5 Gy), 7.55 (4 , 2H, 3-- 1.7 and 8.8 HT), 7.30 (4, IN, 7- 2.9 g), 7.17 (4, IN, 12 2.9 and 8.8 Гп) , 6.88 (0, 28, 12 ko 8.8 Go), 6.77 (Y, 1H, Re 8.8 Hn), 5.38 (5, 2), 4.24-4.20 (t . M2-(4- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-14-(3-phenyl-1,2,4- isopropoxyphenyl)-M4-14-(3-methyl-1,2, 4-|oxadiazol-5-yl)methyleneoxyphenyl|-2,4-pyrimidinidiamine, 5-fluoro-M2-4-se oxadiazol-5-yl)methyleneoxyphenyl-2,4- isopropoxyphenyl)-M4-(4-(3- methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine pyrimidinediamine is obtained in the form of small solid flakes as a result of the reaction of 2-chloro-5-fluoro-M4-14-(3-methyl- 1,2,4-oxadiazol-5-yl)methyleneoxyphenyl|-4-pyrimidinamine and 4-isopropoxyaniline. TN NMR (PM50-96): 10.11 (bg5, IN, 9.72 (bi 5, 1), 8.125 , 1H, 22: 5.3 Hn), 7.61 (49, 2H, 72 8, 8 Hn), 7.34 (4, 2H, I: 7.3

Hz), 7.01 (4, 2H, I- 8.8 Gy), 6.84 (4, 2H, 7- 8.8 Hz), 5.47 (5, 2H), 4.54 (septet, IN, i- 5.8 i), 2.34 (8, ZNU, 1.23 (a, 6Н, 3- 6.4 Pi); РХ/MS: retention time: 24.31 minutes; purity: 9695; MS ( mass/charge): 451 (MN).

F) ko 60 b5

7.3.394 ko35145: M2-4(3,4-styrenedioxyphenyl)-3- | Similarly to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-IM2-144(3-phenyl-1,7,4- fluoro-Ма4-14-(3-methyl-1,2,4-oxadiazole-3- | oxadiazole- 5-yl)methyleneoxyphenyl|-2,4-pyrimidineliamine, M2-(3,4-yl)methyleneoxyphenyl|-2,4-ethylenedioxyphenyl)-5-fluoro-M4-14-(3-methyl- 1,2,4 -oxadiazole-5-tyrimidinediamine yl)methyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-H4-(3-methyl-1,2,4-oxadiazole-5 -yl)methyleneoxyphenyl|-4-pyrimidinamine and 3,4-ethylenedioxyaniline. IN YAM (0M50-46): 710.81 (bg 5, 18), 9.67 (be 5, IN), 8.13 (4, IN, ze 4.7 Hz), 7.63 (40, ЗB ze 41 and 8.8 Hz), 7.07 (t, 1H), 7.00 (d, 2H, I- 8.8 Hz), 6.89 (j, 1H, 2: 8.8 Hn), 6.76 (0, 1H, 4-8.8 Gy), 5.46 (5, 2H), 4.22-4.18 (13, 4H), 2.34 (in, ЗН); LC/MS: retention time: 21.54 minutes; purity: 97; MS (mass/mass): 451 (MN). 7.3.395 K935146: 5-fluoro-M2-(2- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-(4-(3-phenyl-1,24- methoxycarbonylbenzofurav-5-yl)-M4 -14-|oxadiazol-5-ia)methyleneoxyphenia|-2,4-pyrimidinediamine, 5-fluoro-M2-(2-706 (3-methyl-1,2,4-oxadiazole-5-methoxycarbonylbenzofuran5-11)-M4 -14-4(3-methyl»1,2,4-oxadiazol-5-yl)methyleneoxyphenyl|-2,4-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-pyrimidinediamine 5-fluoro -M4-(4-(3-methyl-1,2,4-oxadiazol-5-ip)methyleneoxyphenyl|-4-pyrimidinamine and 2-methoxycarbonyl-5-aminobenzofuran. IN NMR (OM50-4a6); 814 (y, IN, 3 4.7 Сc), 8.02 (5, IN), 7.63-7.56 (t, 58), 7.02 (4, 2Н, 1-2 8.8 Сy), 5, 47 (5, 2H), 3.85 (5,

ZN), 2.34 (5, ZN); LC/MS: retention time: 22.46 minutes; purity: 9795; MS (mass/charge): 491 (MH Kc), 7.3.396 935147: 5-fluoro-M2-(3-tidrocophenyl). | Similarly to the preparation of 5-fluoro-IM4-(3-hydroxyphenyl) M2-14-(3-phenyl-i,2,4-

Ma-(4(3-methyl-1,2,4-oxadiazol»5»oxadiazol-5-yl)methyleneoxyphenyl-2,4-pyrimylindiamine, 5-fluoro-M2-(3-ylumethyleneoxyphenyl|-2,4- hydroxyphenyl )-shch4-H4-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl |-2,4-pyrimidinediamine pyrimidinediamine in the form of small flakes of the product obtained as a result of the reaction of 2-chloro-5-fluoro-m4 -(4-4(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl)-4-pyrimidinamine and 3-tihydroxyaniline. IN YAM? (PM5O-y06): 28.11 (d, TA, 12: 4,6

Gy), 7.66 (0, 2H, 12 5.8 Gy), 7.06-6.97 (p, 5H), 6.42-6.40 (7) (t, 1H), 5.46 (5, 2Н), 2.35 (in, ЗН; RHLMS: retention time: 19.00 minutes; purity: 9599; MS (mass/charge): 409 (МН... 7.3.397 КО35148: М2-(3 ,4-ethylenedioxyphenyl)- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-14-(3-phenyl-1,2,4-ma-(4-(0-ethoxycarbonyl-1-oxadiazole-5 -yl)methyleneoxyphenyl|-2,4-pyrimidicdiamine, M2-3,4-methyl)styliphenyl|-5-fluoro-2,4-ethylenedioxyphenyl)-M4-(4-((1-ethoxycarbonyl-1-methyl)ethylphenyl) -5-fluoro-2,4- pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 2-chloro-14-

Hetoxycarbonyl(dimethyl)methylphenyl|- 5-fluoro-2,4-pyrimidinamine and 3,4- ethylenedioxyaniline. IN NMR (YUM5O0-46): , 3: 8.8 Gy), 7.29 (a, 1H, 1-2.3 Ga), 7.23 (a, 2H, 1- 8.8 Gy, 6.98 (44, 1H, 2: 2.1 and 8.8 Ga), 6.66 (4. 1H, 8.2 Hm); 4.19-4.15 (tp, 4H), 4.07 (db 2H, He) 1-7, Go), 1 ... 7.3.398 Ko935150: M2-(4-(01-ethoxycarbonyl-14) Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-14-(3-phenyl-1,2,4-methyl)styl|phenyl |-5-fluoro-M4-(4-oxadiazol-5-yl)methyleneoxyphenium|-2,4-pyrimidinediamine (or M4-(3,4-(se) isopropoxyphenyl)-2,4-pyrimidinediamine ethylenedioxyphenyl)-5- fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine), M2-I14-K1-ethoxycarbonyl-1-methyl)ethyl|phenyl)-5-fluoro-M4-(4-isopropoxyphenyl)-2,4- b pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(4-isopropoxyphenyl)-4-pyrimidinamine and 4-Hetoxycarbonyl(dimethyl)methyl|aniline.

IN NMR (0M8O-4bu: 129.18 (g 5, MH), 91 (be 5, 1), 8.01 (0, 1H, 52 3.5 Gy), 7.56 h (d, 25, 3 - 8.8 Hn), 7.54 (6, 2H, 1- 8.8 Hz), 7.09 (4, 2H, 1-: 8.8 Gy), 6.86 (0, 2H, 12 8 ,8

Hn), 4.56 (septet, IN, 32: 5.8 Hz), 4.02 (di, 7H,, 1 7.0 Go), 1.43 (5, 6NU, 1.26 (y, 68, 3 se 7.0 Gy), 1.09 (5, ZN, I: 7.0 Gah; LC/MS: retention time: 28.49 minutes; purity: 9895; MS (mass/charge): 453 (MNE). so 17.3.399 8935179: M2-1442,3- Analogous to 144-(3,4-ethylenedioxyphenyl)-5 "fluoro-M2-(3-dihydroxypropoxy)phenyl|-M4-(3,4-hydroxyphenyl)-2, 4-pyrimidinediamine, 42-(14-(2,3-dihydroxypropoxy)phenyl|-Ma» ethylenedioxyphenyl)-5-fluoro-2,4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained pyrimidinediamine as a result of the reaction of 2-chloro-5-fluoro-M-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine and 4-(2,3-dihydroxypropoxy)aniline. NR NMR (PM50-а6): 129.09 (in , IN), 8.95 (5, IN), 7.98 " (4.18, 1-35 Hz), 7.51 (а, 2Н, 1- 8.8 С), 7.32 (4, 1, 2.3 Sy), 7.17 (a, GA, 3-23 and 8.8 Hz), 6.77 (44, ЗН, 1- 8.8 Гм), 4.90 (y, 1Н, 7- 5.3 Gy), 4.64 0, 1H, 7- 5.8 Hz), 4.23-8.19 (pz, AN), 3.91-3.89 (t, 1H, 3.80- 3.73 (t, 2H), 3.41 (2H, 22 53 Gu; - s РХ/MS: duration of immersion: 15.04 minutes; purity: 9695, MS (mass/charge): 429 (Mn. " - 7.3.400 K935180: M2-4-02,3- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- " dihydroxytropoxyphenylI-5-fluoro-Scha4-(3- | hydroxyphenyl )-2,4-pyrimidinediamine, 142-(4-(2,3-dihydroxypropoxy)phenyl-3-fluoro-hydroxyphenia)-2,4-pyrimidinediamine Ma-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of reaction 2 -chloro-5-fluoro-M-(3-hydroxyphenyl)-4-pyrimidinamine and 4-(2,3-dihydroxypropoxy)aniline.

IN NMR (0M50-y6): 119.38 (5, 1NI), 9.18 (5, 1), 8.98 (5, EN), 8.12 (4, TN, 7- 3.5 Gy) , about 7.58 (0, 2, 12 8.8 Gy), 7.224, 1H, 1-2.3 Hz), 7.12 (49, 231, 1-2: 2.3 and 8.8 Gl) . , 1 5.8 v), 3.92-3.89 (t, 1H), 3.79-3.74 (tp, 2H), 3.44 y, 2H, 1- 5.3 Hz); LC/MS: duration

Ckz retention: 12.79 minutes; purity: 8995; MC (mass/charge): 387 (MN). 7.3.401 K935175; M2-(4-(2,3-) Similar to the preparation of M4-(3,2-ethylenedioxyphenyl)-5-fluoro-M2-(3- - dihydroxypropoxy)phenyl|-5-fluoro-M4-(4- | hydroxyphenyl)- 2,4-pyrimidinediamine, M2-(4-(2,3-dihydroxypropoxy)phenyl|-5-fluoro-isopropoxyphenyl)-2,4-pyrimidinediamine | M4-(4-isopropoxyphenia)-2,4-pyrimidinediamine is obtained as a result reactions 2" (Se) (42)

Ф) ko 60 b5 chloro-5-fluoro-M-(4-isorgoxyphenyl)-4-pyrimidinamine and 4-(2,3-dihydroxypropoxy aniline): IN NMR (PM5O-abu 119.12 (5, 1), 8, 91 (5, IN), 7.97 (d, 1H, 2-3.5 Hz). 7.580, 2H, 1- 8.8 Gy), 7.494, 2H, 3- 8.8 Hn), 6.85 (d, 2H, 1-8,8

Go), 6.76a, 2, 2- 85.8 Hz); 4.89 (4, IN, 2: 4.7 Hz), 4.63 (b 1H, 22: 5.2 Hn), 4.56 (septet, IN, 7-: 5.8 Gy), 3, 90-3.89 (t, IN), 3.76-3.73 (t, 2H), 3.51 (i, 2H, 1: 5.3 Hz), 1.25 (8, BN, 312: 5, 8 Gi); LC/MS: retention time: 17.48 minutes; purity: 9895;

MS (mass/charge): 429 (MY B). 7.3.202 Ko35169: M4-14-K1-ethoxycarbonyl-1- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro -M2-(3- methyl)ethyl|phenyl-5-fluoro-M2-(3 - tihydroxyphenyl)-2,4-pyrimidinediamine, M4-14-C 1-ethoxycarbonyl-1-hydroxyphenyl)-2,4-pyrimidinediamine methyl)ethylphenyl|-5-fluoro-M2-(3-hydroxyphenyl)-2,4- pyrimidinediamine is obtained as a result of the reaction of 2-chloro-MA-(4-Cy-ethoxycarbonide-1-methyl)styliphenyl|-5-fluoro-4-pyrimidinamine and 3-aminophenol. IN NMR (OM 50-46): 727.87 (4, IN, 2: 3.5 Hz), 70 7.56 (8, NI, 12 8.8 Hz), 7.35 (d, 2H, 1 : 8.8 Hz), 7.25-7.23 (t, IN), 7.08 (4, IN, 1-82

Go), 6.91 (40, EN, 7-23 Gy), 6.83 (0, 1H, 3-- 7.6 Hz), 6.50 (49, IN, 1- 1.7 and 8, 2 Gy), 413 (dn, 3 7.0 Hz, 1.58 (5, 6H), 1.19 (i, ZN, 1: 7.0 Hz); РХ/MS: retention time: 22.97 minutes ; purity: 9890; MS (mass/mass): 411 (MNK). 7.3.403 K935164: 5-fluoro-M444- Similar to the preparation of M4-(3,4 ethylenedioxyphenyl)-5-fluoro -M2-(3-

Isopropoxyphenyl)-M2-K(M-methyl-2-hydroxyphenyl)-2,4-pyrimidinediamine, the required product of 5-fluoro-M4-(4-methoxycarbonyl)ipyrrole-4-yl-2,4- isopropoxyphenyl)- M2- 1(0-methyl-2-carbomethoxy)pyrrole-a-ia|-2,4-pyrimidinediamic pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine, 2-chloro-5-fluoro-MA-(4- isopropoxyphenyl)-4-pyrimidinamine and M-methyl-2-methoxycarbonyl-4-aminopyrrolehydrochloryl with the addition of diisopropylethylamine. IN NMR (SOSIZ): 017.87 (Bu 5, 1H), 7.44 (0, 2H, 12 8.8 Go), 7.08 (Bg 5, IN), 6.99-6.85 (t , ЗН), 6.70 (y, 1Н, 1-2.3 Hz), 6.63 (d, IN, 3--1.7 Hz), 4.52 (septet, 1Н, /- 5.8 Hn), 3.80 (5, ЗН), 3.79 (5, ЗН), 1.34 (y, 6Н, 52: 5.8 Hz); LC/MS: retention time: 23.89 minutes; purity: 9995; MC (mass/charge) in: 400 (MN). 7.3.494 K935165: 5-fluoro-M2-(4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- isopropoxyphenyl)-M4-|(M-methyl-2-hydroxyphenyl) -2,4-pyrimidinediamine, 5-fluoro-M2-(4-isopropoxyphenyl)-M4-KM-carbomethoxy)pyrrol-4-yl|-2,4-methyl-5-carbomethoxy)pyrrol-4-yl|-2 ,4-pyrimidinediamine is obtained as a result of the reaction of pyrimidinediamine with 2-chloro-5-fluoro-H4-(N-methyl-2-carbomethoxypyrrol-4-yl)-4-pyrimidineamine and 4-isopropoxyaniline. IN NMR (SOSIZU: 117.84 (y, 18, 72 2.3 Hz), 7.360, 2H, 1 8.8 g), 7.224, 1H, 1 I Gy), 6.87 (4, 2H, 12 8 .8 Hz), 6.845, INNU 677 (4, 1 1.7 C), 6.61 (g 5, IN), 4.49 (septet, 1H, 7: 5.8 Gy), 3.82 (6 . ): 400 (MAN U). o 7.3.405 B935166; M2-(3,4-ethylenedioxyphenyl)-5- ! Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- fluoro- m4-(0H-methyl-2-hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-M2-(3,4-ethylenedioxyphenyl)-M4-HOM-methoxycarbonyl)pyrrol-4-yl|-2,4- methyl -2-carbomethoxy)pyrrole-4-1l1-2,4-pyrimidinediamine is obtained as a result of the reaction of pyrimidinediamine with 2-chloro-5-fluoro-M4-(M-methyl-2-methoxycarbonylpyrrole2-yl)-4-pyrimidinediamine and 3,4 - styrene dioxyaniline. 1H NMR (SOSIS): 0 7.84 (4, 1H, 7 3.5 "se

Gu 7.34 (5, 18), 7.21 (5, 1), 6.82 (9, 2H, 2: 8.8 Gy), 6.76 (0, 2H, 1- 8.8 Hz), 6 .58 (5,

Зо 1Н),4.27-4.18 (t, 4НИ), 3.90 (в, ЗН), 3.81 (з, ZNU; RH/MS: retention time: 20.02 minutes; purity: 9395; MC (mass/charge): 400 (MN). b» 7.3.406 K935167: М4-14-ЦИ-ethoxycarbonyl-|- Similar to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-(3- methyl)ethylphenyl1-5-fluoro-M2-(4-hydroxyphenyl)-2,4-pyrimidinediamine, M4-|4-C1-ethoxycarbonyl-1-h- isopropoxyphenia)-7,4-pyrimidinediamine methyl)ethyl|phenyl|- 5-fluoro-M2-(4-isopropoxyphegenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(4-|1-ethoxycarbonyl-1- sem methyl)styliphenyl|-5-fluoro-4-pyrimidinamine and 4-isopropoxyaniline. IN NMR (pM50-06): 19.29 (5.1, 8.95 (8, 1H), 8.02 (9, IN, ze 4 Hyd), 7.68 (4, 2H, 3-8, 8 p

Go), 7.46 (3, 3H, 1: 8.8 Gy), 7.224, 2H, 72: 8.8 Hz), 6.75 (0, 2H, 22 8.8 Hz), 4.48 ( septet, IN, 7- 5.8 Hz), 4.04 (di, ЗН, 1- 7.0 Hz), 1.47 (5, 6Н), 1.22 (4, 6Н, 1- 5.8 Gi), 119, ZN, Her 7.0 Hz); LC/MS: retention time: 28.11 minutes; purity; 9995;

MC (mass/charge): 453 (MN.k). 7.3.407 K935159: 5-fluoro-M4-4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M4-|3-" isopropoxyphenyl)-M2-(4-hydroxyphenyl|-pyrimidine-2, 4-diamine, 5-fluoro-m4-(4-isopropoxyphenyl)-M2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4- | methoxycarbonylmethyleneoxyphenyl)-2.4-pyrimidinediamine is obtained as a result of the reaction of pyrimidinediamine with 2-chloro-3-fluoro-M4 -(4-isopropoxyphenyl)-4-pyrimidinamine and methyl-4-s aminophenoxyacetate. IN NMR (SOSIZU: С17.88 (0, 1Н, 1- 3.5 Hz), 7.46 (4, 2Н, 1- 8.8Н). 7.42 (y, 2Н, 1-88 Hz), 6.38 (4, 2, 1- 9.3 Hz), 6.85 (4, 2H, 1: 9.3 Gy), 6.78 (h p z» 5, IN), 6.63 (Bk y, IN, 22 2.3 Gy) . ; LC/MS: retention time: 73.19 minutes; purity: tk MS (mass/charge); 427 (MH). 7.3.408 8935157: M4-(4-(1-ethoxycarbonyl) 1- Analogous to the preparation of M4-( 3,4-ethylenedioxyphenyl)-5-fluoro-IM4-(3-methyl)ethyl|phenyl|-5-fluoro-M2-(4-hydroxyphenyl|-pyrimidine-2,4-diamine, M4-(4-I( 1-stoxycarbonyl-1-(ee) methoxycarbonylmethyleneoxyphenyl)-2,4-|methylethyl|phenyl)|-5-fluoro-M2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4- pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4 -14-|1-ethoxycarbonyl- with 1-methyl)ethyl|phenylI-5-fluoro-4-pyrimidinamine and 4-(methoxycarbonylmethyleneoxy)anisine. 1H NMR(SOSIS): C 7.92 (5, 1H), 7, 55 (y, 2H,1- 8.7 Hz), 7.43 (y, 2H, 1- 9.3 Gy), 7.33 (8, 2H, 1-5 8.7 1), 6.87 (8 , 2H, 1- 9.3 Gy), - 5.79 (5, 18), 6.73 (a, 18, 1- 2.3 Hz), 4.62 (5, 2H), 4.13 (di, 2H, /- 7.0 Hn), 3.81 (5, 3H), 1.59 (8, 6H), 1.20 (i, ЗН, 7.0 Gy); LC/MS: retention time: 25.20 minutes; (Se) 42) ko 60 b5 шИИИИШ02520ОО020200000002000001 PP ren ol Msfnsanavnu YaMU, 7.3. 409 Kk9z35152: M2-14-K1-ethoxycarbonyl-1- Similar to the preparation of IM2-14-(1-ethoxycarbonyl» 1-methyl)ethyl)phenia|-5-fluoromethyl)ethyl|phenyl|-5-fluoro-M4- (3- 4-(44isopropoxyphenyl. 2,4-pyrimidinediamine, M2-(4-((1-ethoxycarbonyl-1- hydroxyphenyl)-2,4-pyrimidinediamine methyl)ethylphenyl|-5-fluoro-M4-(3-hydroxyphenyl )-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-Ma-(3-hydroxyphenyl)-1-pyrimidinamine and 4-(1-ethoxycarbonyl-1-methyl)ethylaniline. TN NMR (SOSIS): (17.89 (8, 1H, /- 2.9 Gy), 7.24-7.10 (t, 5H), 6.93 (0, 1H, 1-- 7.6 Gy), 6.68 (0, 2H, 1- 8.2 Hz), 4.08 (actions, 2H, 2-70

Gy), 1.52 (5, ZN), 1.49 (in, ZNU, 1.16 (ii, ZN, 24-7.0 Hz); LC/MS: retention time: 22.15 minutes; purity; 9695; MS (mass/charge): 411 (MNK), 7.3.419 M2-(3-tert-butylphenyl)-5-fluoro-M4-(3- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5- fluoro-M24(3-thydroxyphenyl)-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, M2-(3-tert-butylphenyl)-5-fluoro-M4-(13-4K940257) hydroxyphenyl)-2,4 -pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-7170 M-(3-hydroxyphenyl)-4-pyrimidineamine and 3-tert-butylaniline. LC/MS: retention time: 23.82 minutes; purity: 10095; MC (mass/charge): 353 (MN); 19 NMR (SOSIS): 7 7.96 (IN, 4, 22 3 Gy), 7.61 (1H, aa, 3-7.5; 2.2 and 0.9 Hz), 7.49 (IN, -72.5 tsu 7.27 (NN, t), 7.18 IN - 8 Go), 7.99 (IN, t), 6.94 (IN, 5), 6.91

CH, ad, 1-7.5 and 2.5 Hyd), 6.80 (IN, y, 2-5 7.5 Hz), 6.72 (2H, pt), 6.58 (IN, dad, 1 7.5; 2.5 and 0.9 Hz), 6.52 (1H, aa, 1-7.5; 2.5 and 0.9 Gy), 1.28 (9H, 5). 7.3.4 144-(3-chloro-4-thihydroxy-5-methylphenyl)-5- | Similarly to the preparation of 1Ch44(3,4-ethylenedioxyphenyl)-3-fluoro-M2-(3-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidonediamine, sumine 14Ch4-(3-chloro-4-hydroxy-5- methylphenyl)- methoxycarbonylmethyleneoxyphenyl)-2,4- | 5-fluoro-M243-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and M4-(3-pyrimidinediamine and M4-(3-chloro-4-chloro-4-hydroxy-5-methylphenyl)-M2-(3-ethoxycarbonylmethyleneoxyphenyl)- 5-fluoro-tihydroxy-5-methylphenyl)-M2-(3-2,4-thyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-chloro-4-stoxycarbonylmethyleneoxyphenyl)-5" hydroxy-5 -methylphenyl)-4-pyrimidinamine and ethyl-3-aminophenoxyacetate. LC/MS: fluoro-2,4-pyrimidinediamine (940258) retention time: 20.34 minutes (CO2MEe); purity: 1795; MS (mass/charge): 432 (M; LC/MS: retention time: 21.83 minutes; purity 7892; MS (mass/charge): 446 (ME). 7.3.412 M2-(3-tert-butylphenyl) -M4-(3,4- Similar to the preparation of M4-(3,4-ethylenedioxypheny)-5-fluoro-M2-(3-dimethoxyphenyl)-5-fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2 -(3-tert-butylphenyl)-M4-(3,4-pyrimidinediamine (K940260) dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3,4 -dimethoxyphenyl)-4-pyrimidinamine and ethyl-3-tert-butylaniline. LC/MS: retention time: 24.87 minutes; purity: 9995; MS (mass/charge): 397 (MH); IN NMR (SRSIZ): 7.92 (IN, d, 7:34 Gi), 7.501 H, 4, 1-8 Hn), 7.28 (1H, 6 2.3 Sy), 7.21 (NN, 4, 2-8 Hz), 78 (1H, t), 7.08-7.01 (2H, sem tt), 6.99 (1H, 5), 6.84 (21, 4, 1-9.2 Gy), 6.65 ( 1H, 5), 3.89 (ZH, 5), 3.72 (ZH, 5), 1.26 t 2 0 TO ol le eh L..02 26. A 5 ( ( ЖЖ 6 2 9 ( 5 ( "5 Sh - l 1.7 7 shchi 7.3.413 M2-(2-(M-benzylpiperazine)styli|-5- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- fluoro-Sh4 -(3-hydroxy iphenyl)-7,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(2-(-benzylpiperazine)stil|-5-fluoro-M4-pyrimidinediamine (8940261) (3-tihydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-Ma-(3-hydroxyphenyl)-4-pyrimidinamine and 4-(4-benzylpiperazine)stylamive. (That

LC/MS: retention time: 17.15 minutes; purity: 90 99; MS (mass/charge): 422 (M, 423 (MNE); IN NMR (SOSIS): (18.42 (1H, 5), 7.82 (1H, 4, 12 3.9 Hz), 7.32 -7.08 (6H, t), 6.73 (1H, 5), 6.61 (1H, 49, 3: 8.1 and 2.1 Go), 6.51 (IN, y, 7: 7 ,5 Gi), Z, (EN, b» 5) 3.59 (IN, t), 3.02 (2Н, t), 271-241 (38, p), 2.10-1.16 (5Н . -5-fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(2-(M-benzylpiperazine)ethyl|-M4-(3,4-pyrimidinediamine (2940262) dimethoxyphenyl)-5-fluoro-2 ,4-pyrimidinediamine is obtained as a result of the reaction of 2-sem chloro-5-fluoro-M4-(3,4-dimethoxyphenyl)-4-pyrimilinamive and 44(M-benzylpiperazine)stilamine. LC/MS: retention time: 17.48 minutes ; c purity: 99 95; MS (mass/charge): 466 (M-k), 467 (M); IN NMR (SOSIS); 0 7.82 (IN, 0.1-3.9 ih), 7 .44 (IN, 5), 7.33-7.10 (6H, t), 7.04 (IN, ad, 1-8.9 and 2.5 Hz), 6.84 an, af 3-89 Gi), 6.58 (1H, 5), 5.40 (IN, 5), 3.91 (ZH, 5), 3.87 (ZH, 5), 3.91 (2H., t), 2.87 (2H, t), 2.51 (ZN , pt), 1.80 (2H, t), 1.60 (4H, t), 1.30 "IN, t). 7.3.415 42-(4-(M-benzipiperidino)|-M4-(3,4- Analogous to the preparation of M4-(3,4-ethylenedioxypheny)-5-fluoro-IIM2-(3» « dimethoxyphenyl)-5-fluoro -2,4-tihydroxyphenyl)-2,4-pyrimidinediamine, M2-14-(M-benzylpiperidino)|-M4-(3,4-pyrimidinediamine (5940263) dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained in resulting from the reaction of 2-chloro-5-fluoro-Mn4-(3,4-dimethoxyphenyl)-4-pyrimidinamine and M-benzyl-4-c aminopiperidine. LC/MS: retention time: 15.52 minutes; purity: 99,995 ;

MS (mass/charge): 438 (MN-R; IN YAM? (SRSIZU: 07.81 (IN, 4, 3.3 Gy), 7.35-7.18 h (ZN, t), 7.10 (1, 44, 12 8.7 and 2.6 Gy), 6.84 IN, y, 3e 8.7 Hz), 6.56 (1H, 5), 4.73 PN, i t 4.32 6 .9 Gy), 3.89 (5H, 5), 3.75 (IN, po), 3.51 (2H, t), 2.81 (2H, t), 2.15 (2H, t), 2.00

OH, t), 1.66-1.44 (4H, t). 7-3.416 M2-44(M-benzylpiperidino)|-5-fluoro- Similar to the preparation of M44(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-

M44(3-hydroxyphenyl)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, IM2-(4-(M-benzylpiperidino)|-5-fluoro-Mach(3-

Go! Pyrimidinediamine (KO40264) hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro»

Mma43-hydroxyphenyl)-4-pyrimidicamine and M-benzyl-4-aminopiperidine. RH/MS. duration of seizure: 14.00 minutes; purity: 96 95; MS (mass/charge): 394 (MK), ko 395 (MINNYA); 1H NMR (SOS): 217.81 (IN, d, 15 3.6 Hn), 7.40-7.28 (5H, t), 7.21-74 (2H, t), 6.69 (IN , t), 6.62 (IN, t), 6.59 (1H, t), 5.20 (1H, 5), 3.65 (2H, 5), 3.50 (IN, - 5), 3.03 ( 1H, p), 2.83 (IN, tu, 2.13 (1, pt), 1.95-1.70 IN, t), 1.58 (49, t). (Se) 42) ko 60 b5

7.3.A17 M4-(3-tert-butylphenyl)-M2-(3- Analogously to the preparation of 1Ch4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3- ethoxycarbonylmethyleneoxyphenyl)-5- hydroxyphenyl)-2,4 -pyrimidinediamine, M4-(3-tert-butylphenyl)-M2-(3-fluoro-2,4-pyrmidinediamine (K940270) cetoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinethiamine is obtained as a result of the reaction M4-(3-tert -butylphenyl)-2-chloro-5-fluoro-4-pyrimidinamine and ethyl-3-aminophenoxyacetate. РЧ/МС: duration of retention; 27.30 minutes; purity: 98 5; MC (mass/charge): 439 (MN); IN NMR (0M50-d6U: 7 9.59 (1H, 5), 9.33 (1H, 5), 8.11 (EN, to, Ia, and 1.8 Hz), 7.81 01H, 4, 77.2 Gy), 7.49(1H, in 24

Gy), 7.30-7.28 (ZN, t), 7.14-7.03 (2H, t), 6.46 (JN 4, 4 7.8 Gy), 4.57 (2H, 5 ), 13 (2Н, а, 7.2 g), 1.239Н, 5) VZN, 12 7.2 Hz). 7-3.418 ma-(3-tert-butynphenyl)-M2-(3-chloro-4- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxy-5-methylphenyl)- 5-fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M4A-(3-tert-butylphenyl)-M2h(3-chloro-4-pyrimidinediamine (K940271I) hydroxy-5-methylphenyl)-5-fluoro- 2,4-pyrimidinediamine is obtained as a result of the 70 reaction of MA (3-tert-butyphenyl)-2-chloro-5-fluoro-4-pyrimidinamine and 3-chloro-4-tihydroxy-5-methylaniline. RF/MS: retention time: 25.46 minutes; purity: 100 95; MS (mass/charge): 400 (M.U); IN NMR (0M50-95); AND? 9.63 (IN, 5), 930 1, 5). 8.82 (1H, 5), 8.20 (1H, 4, 2- 3.9 Gy), 7.92 (IN, 4, 22 8.8 Gy), 7.58 (7H, t), 7.40 - 7.20 (ЗН, т) 2.22 (З3Н, 5), 1.35 (9Н, 5). 7.3.9 M2-(3-tert-butylcarbonylaminophenyl)- Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M24(3-

Ma-(3-hydroxyphenia)-5-fluoro-2.4-hydroxyphenia)-2,4-pyrimidinediamine, M2-(3-tert-butylcarbonylaminophenyl)- M4-(3-pyrimidinediamine (K940275) hydroxyphenyl)-5-fluoro-2 ,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine and 3-butylcarbonylaminoaniline.

LC/MS: retention time: 20.19 minutes; purity; 91 36; MS (mass/charge): 396 (MH; IN NMR (OM5O0-96u: CO 9.42 (1H, 5), 9.28 (IN, 5), 9.21 (IN, 5), 9.18 ( 1H, 5), 8.17 (IN, 0.12 3.9 Hz), 7.90 PIN, 53, 7.55 (18, di, 326.9 and 21 Hn), 7.51 (IN, 8, 1 7.8 and E.5 Gy), 7.26-7.13 (AN, t), 6.57 (1H, 4d, 3-7.5 and 1.5 Hz), 1.30 (OH, 5 ). 7.3.420 Ma4-(3,3-dihydroisobenzofuranyl-1-one-b- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2-(3-yl)»5-fluoro-M2 -(2- Bugoxyphenyl)-2,4-pyrimidinediamic, M4-(3,3-dihydroisobenzofuranyl-1-one-6-1l)-5-methoxycarbonylbenzofur-5-115)-2,4- fluoro-M2-(2 -methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine is obtained in pyrimidinediamine KU40294 as a result of the reaction of 2-chloro-M4-(3,3-dihydroisobenzofuranyl-1-one-6-yl)-5-fluoro-4-pyrimidinamine and 2 -methoxycarbonyl-3z-aminobenzofuran.. LC/MS: retention time: 21.34 minutes; purity: 97 90; MS (mass/charge): 434 (Mk); IN YAM? (РМ50-46): (7 9, 90 (1H, 5), 9.61 (18, 5u, 8.4-8.12 (AN, t), 7.35-7.67 (4H, t), 5.50

СН, 5), 3.98 (ЗН, 5).

M2-(3-ethoxycarbonylmethyleneoxyphenyl|- | Similar to the preparation of IM4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3- sem

M4-(3,3-Dihydroisobenzofuranyl)-one-b-tihydroxyphenyl)-2,4-pyrimidineliamine, M2-(3Z-ethoxycarbonylmethyleneoxyphenyl)-M4-yl)-5-fluoro-2,4-pyrimidinidiamine K940285 | (3,3-digylroisobenzofuranyl-1-one-b-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,3-dihydroisobenzofuranyl-1-one-b-yl) )-5-fluoro-4-pyrimidinamine and ethyl-3-aminophenoxyacetate. LC/MS: retention time: 20.55 minutes; purity: 76 95; MS (mass/charge): 438 (Mk). 440 (MH), 1 NMR (0M50-46): 9.70 (IN, 5), 9.30 (IN, 5), 8.23-8.06 (IN, t), 8.05 1H, 5, 7-63 (1H, y . (2Н, 5), 4.60 (28, 5), 4.13 (2Н, 4, 2-72 Го), 1.18 (3Н, у, 1 7.2 Hz). 7.3.422 M2-(3,5-dimethoxyphenyl)-M4-(3- Analogous to the preparation of IM4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- b» ethoxycarbonylmethyleneoxyphenyl)-5- tihydroxyphenyl)-2 . chloro-M4-(3-stoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidinamine and 3,5-dimethoxyanitne. LC/MS: retention time: 24.12 sem minutes; purity: 8690; MC (mass/charge): 443 (MN.

Z5 7.3.423 MA-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-1h2-(3- (se) (3-trifluoromethylphenyl)|-2,4- hydroxyphenyl)-2.,4-pyrimidinediamine, M4-(3, 4-ethylenedioxyphenyl)-5-fluoro-M2-(3-pyrimidinediamine (K926805) trifluoromethylphenyl)-2,4-tyrimylinliamine is obtained as a result of the reaction of 2-chloro-

Mma-(3,4-ethylenedioxyphenia)-5-fluoro-4-pyrimidinamine and 3-trifluoromethylaniline.

РЧ/МС: duration of retention; 25.88 minutes; purity: 8975; MS (mass/charge): 407 (Mn. « 7.3.424 M2-(2-ethoxycarbonylindol-7-1l)-Ma4- Analogously to the preparation of Me-(3,4-ethylenedioxyphenine)-5-fluoro-m2-(3- (3,4-ethylenedioxyphenyl)-5-Fluoro-2,4-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(2-ethoxycarbonylindole-7-1l)-M4-(3,4- pyridinediamine (8926808) ethylenedioxyphenyl )-5-fluoro-2,4-pyridinediamine is obtained as a result of the reaction of 2-chloro-M4-3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 2-ethoxycarbonyl-7-aminoindole. РЧ/МС: duration of retention; 24.11 minutes; purity: 8895, MS; - "mass/charge): 450 (MN). 7.3.425 ma-(144(4,5-dichloro-1H-imidazole-1- Analogously to the preparation of 144-(3,4-ethylenedioxyphenyl)-5-fluoro-2-(3-yl)phenyl-5-fluoro-M2 -(3- thydroxyphenyl)-2,4-pyrimidinediamine, M4-(4-(4,5-dichloro-1H-imidazole- and «lphenyl) |-5- ethoxycarbonylmethyleneoxyphenyl)-2,4- fluoro-m2-( 3-ethoxycarbonylmethineoxyphenia)-2,4-pyrimidinediamine is obtained in pyrimidinediamine (K926809) as a result of the reaction of M-4-H444,5-dichloro-1H-imidazole-I"ip)phenyl|-2-yur-5-fluoro-4- (ee) pyrimidineamine and ethyl-3-aminephenoxyacetate. LC/MS: retention time: 25.22 tip, purity: 7725; MS (mass/charge): 519 (MN. ko 7.3.426 M443,4-ethylenedioxyphenyl)-5 -fluoro-M2- Similar to the preparation of M4-(3,4-ethylenedioxyphenia)-5-fluoro-M2-(3-

I(3-01,3-oxazol-5-ilufenia |-2,4- hydroxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-/3- shk pyrimidinediamine ( 926813) (1,3-oxazol-z-yl)phenyl!-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-1M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3-( 01,3-oxazol-5-(Ce) 42) ko 60 b5 yl) aniline. LC/MS: retention time: 20.25 minutes; purity: 8195, MS (mass/charge): 406 (MNK. 7.3.427 42-(2-stoxycarbonylindol-7-yl)-5-fluoro- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro -M2-(3-ma-(3-thihydroxyphenyl)-2,4-pyridinediamine | hydroxyphenyl)-2,4-pyrimidinediamine, M2-(2-ethoxycarbonylindol-7-yl)-5-fluoro M4-(8926814) ( 3-hydroxyphenyl)-2,4-pyridinediamine is obtained as a result of the reaction of 2-chloro-3-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine and 2-ethoxycarbonium-7-aminoindople.

RU/MS: retention time: 25.4 minutes; purity: 9195. 7.3.428 M24(3-aminophenyl)-Ma-(3,4-44-(3,4-ethylenedioxyphenyl)-2-chloro-5-fluoro-4-pyrimidinamine (50 mg, 0.18 mmol ) ethylenedioxyphenyl)-5-fluoro-7,4- is dissolved in anhydrous MeOH (1 ml), 3-pyrimidinediamine (K950207) zenoanipine (163 mg, 1.2 mmol) is added to the resulting solution, and the mixture is heated in a reflux flask for 4 days (oil bath temperature: 70 oC). After that, the mixture is cooled to 220C, concentrated to dryness under reduced pressure and subjected to carbon chromatography on sinica gel (CHCl3--acetone, 9:1) in order to form M2-(3-aminophenyl)-Mm4-(3,4-styrenedioxyphrenyl) )-5-fluoro-2,4-pyrimidinediamine. IN NMR (SPZOGU): p 7.66 (d0, 1H, I - 3.6 Hz), 7.186, 1A, 15

Hz) 7.09 (5 1H, 15 2.1 Go), 6.80-6.90, (t, 1H), 6.69 (0, 18, 1-2 8.1 Go), 6.57 (ti, IN), 6.20 (t, 1NI), 6.60 (t, IN), 4.10 (ta, 4H); LC/MS purity: 90.79; MS (mass/charge): 354.13 (MA, 109). 7.3.429 Ma-(3,4-ethylenedioxyphenyl)-M2-(3- Analogous to the preparation of M2-(3-aminophenyl)-M4-(3,4-ethylenedioxyphenyl)-5-fluoroethoxycarbonylmethyleneaminophenyl)-5- 2,A4 -pyrimidinediamine, M4-(3,4-ethylenedioxyphenyl)-M2-(3-fluoro-2,4-pyrimidinediamine (K950186) ethoxycarbonylstyreneaminophenyl)-5-fluoro-2,4-trimylindiamine is obtained as a result of the reaction M4-4(3, 4-ethylenedioxyphenyl)-2-chloro-5-fluoro-4-pyrimidinamine and

C-ethoxycarbonylmethyleneaminophenylaniline. LC/MS: retention time: 23.29 minutes; purity: 95.79; MS (mass/charge): 440.41 (MN). 7.3.430 M44(3,5-dichloro-4-hydroxyphenyl)-M24(3- | Analogous to the preparation of M2-(3-aminophenyl)-M44(3,4-ethylenedioxyphenyl)-5-fluoro-stoxycarbonylmethyleneoxyphenyl)-5- 2 . 2-chloro-M4-(3,5-dichlorophenyl-4-hydroxy)-5"-fluoro-4-pyrimidicamine and ethyl 3-aminopheoxyacetate. LC/MS: retention time: 22.51 minutes; purity: 96.195; MS (mass/charge): 466.88 (MN). 7.3.431 MA-(3-aminophenia)-5-fluoro-M2-(2- Mixture of Ma-(3-aminophenyl)-2-chloro-5-fluoro-4-pyrimidinamine (10 mg, 0.06 mmol) and Methoxycarbonylbenzofuran-5-yl)-2,4-2-methoxycarbonyl-5-aminebenzofuran (36 mg, 0.18 mmol) is heated in a flask with pyrimidinediamine (KUZO162) under reflux in solvent-free MEON (0.5 ml) for 2 days. (oil bath temperature: 100 0). After that, the sums are cooled to 22 oC. further concentrated to dryness under reduced pressure and subjected to He) column chromatography on silica gel (CHCl3:acetone, 9: 1) in order to form M4-(3-aminophenyl)-5-fluoro-M2-(2-methoxycarbonylbenzofuran-5-yl) )-2,4-pyrimidinediamine. IN NMR (0M50-yb): 0 8.24 (5, 1H), 7.96 (400, 1H, /- 1.7; 3.5

Hz) 7.46-7.59 (t, ZN), 6.93-6.99 (t, 2, 6.84 (9, IN, 7 8.2 Hz), 6.35 (t, 1H) , 3.84 "s (5, ZNU; LC/MS purity: 97.895; M5 (E5) t/s 394.02 (M, 20). 7.3.432 M44(3-aminophenia)-5-fluoro-M2- (3- Analogous to the preparation of M4-(3-aminophenyl)-5-fluoro-M2-(2-b hydroxyphenyl)-2,4-pyrimidinediamine methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, M4- (3-(8950163) aminophekyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(3-aminophenyl)-2-chloro-5-fluoro-4-pyrimidinamine and 3- h of hydroxyniline. IN NMR (0M50-46): Gy 7.94 a, IN, 3-41 Gy), 7.20 (t, 2H)), 6.89- 7.00 (tp, 4H)) , 6.36 (t, 2H); LC/MS: retention time: 11.92 minutes; purity: sem 95.09; MS (mass/charge): 312.09 (MNK).

Zo 7.3.433 Ma-(3-aminophenyl)-5-fluoro-M2-(3- Analogous to the preparation of M4-(3-aminophenyl)-5-fluoro-M2-(2-he) isopropoxyphenyl)-2,4-pyrimidinediamine methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, M4-(3- (8950164) aminophenyl)-5-fluoro-M2-(3-isopropoxyphenial)-2,4-pyrimidinediamine is obtained as a result of MA reaction -(3-aminophanium)-2-chloro-5-fluoro-4-pyrimidinamine and 3-isopropoxyaniline. РХ/MS: duration of freezing: 17.52 minutes; purity: 98.995;

MS (mass/charge): 354.13 (MN). " 7.3.434 M44(3-aminophenyl) 5-fluoro-M2-(4- Analogous to the preparation of M4-(3-aminophenyl)-5-fluoro-M2-(2- isopropoxyphenyl)-2,4-pyrimidinediamine | methoxycarbonylbenzofuran-5 -yl)-5-fluoro-2,4-pyrimidinediamine, Ma-(3» shsh (K950165) aminophenip)-5-fluoro-M2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of M4- (3-aminophenia)-2-chloro-5-fluoro-4-pyrimidinamine and 4-isopropoxyaniline. 1H NMR (0M50-026-MeOO, 300 MG nu: 2 7.90 (0, 1H, re 41 i - Hz) 747 (p 2H), 7.03 (0 IN, 1- 1.7 Go), 6 .60-6.95 (t, UN), 6.29 (t, 1H), 543 (septem, IN, 5: 6.0 Gy), 1.18 (4, BN, 72 6.0 Gy); LC/MS: retention time: 17.11 minutes; purity: 88.49; MS (mass/charge) in: 354.09 (MN). 7.3.435 M2-(3-furylmethylene)-5-fluoro-M4- (3- Similar to the preparation of M4-(3-aminophenyl)-5-fluoro-M2-(2-hydroxyphenyl)-2,4-pyrimidinediamine methoxycarbonylbenhofuran-5-1l)-5-fluoro-2,4-pyrimidinediamine, M2-( 3- (og) (5950210) furyamethylene)-5-fluoro-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-imi4-(3-hydroxyphenyl)-4- pyrimidineamine and 3-cofurnylmethylamine LC/MS: retention time: 16.03 minutes purity: 93595;

MS (mass/charge): 301.10 (MN). -th 7.3.436 5-fluoro-M4-(3-tihydroxyphenyl)-M24(4- Similar to the preparation of M4-(3-aminophenyl)-5-fluoro-124(2-methoxyphenyloxyethinenamino)-2,4-methoxycarbonylbenzofuran-5- 1l)-5-fluoro-2,4-ptyrimidineliamine, 5-fluoro-m4-(3- (Ce) pyrimidinediamine (KU502 11) tihydroxyphenyl)-M2-(4-methoxyphenyloxyethmylenamino)-2,4-pyrimidinediamine 42) ko 60 b5 is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine and 2-(4-methoxyphenyl)stylamine. LC/MS: retention time: 18.88 minutes; purity: 97.65; MS (mass/charge): 371.09 (MNK). 7.3.AZ37 Ma-(3-aminophenyl)-M2-I1M3-1M44(3-M4-(3-aminophenyl) M 2-3 (Pm4-(3-aminophenyl))-5-fluoro-2,4-aminophenia) )-5-fluoro-2,4-pyrimidinediamine|aminophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of pyrimidinediamine|aminophenyl)-5-fluoro- reaction of 2,4-dichloro-5-fluoropyrimidine and 3-aminoaniline . LC/LMS: 2,4-pyrimidinediamine (8950137) retention time: 13.10 minutes; purity; 96.49; MS (mass/charge): 513.01 (MN). 1.4438 M443 A-ethylenedioxyphenyl)-5-fluoro-M2- | M443,4-ethylenedioxyphenyl)-m2-|3-(hydroxyethylamino)phenyl)-5-fluoro-2,4-

IZ-(hydroxyethyleneamino)phenyl-2,4-pyrimidinediamine is obtained as a result of the reaction of M2-(3-aminophenyl)-M4-(3,4-pyrimidinediamine (8950208) stipenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine and 2- bromethanol. LC/MS: retention time: 15.44 minutes; purity: 98.675; MS (mass/charge): 398.05 70 (MN). 7.3.439 M2-(3-bis(hydroxyethyl)aminophenyl-M4- | M2-|3-bis(hydroxyethyl)aminophenyl-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4- (3,4 -ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M2-(3-aminophenyl)-Ма4-(3,4-pyrimidinediamine (2950209) ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine and 2 -bromethanol.. LC/MS: retention time: 15.64 minutes; purity: 97.69; MS (mass/mass): 447.06 (MN). 7.3.4 b-ethoxycarbonyl-M4- Analogous to the preparation of M4-( 3,4-ethylenedioxyphenyl)-5-fluoro-1M2-|3-(ethoxycarbonylmethyl)-M2-(4-hydroxyphenyl)-2,4-pyrimidinediamic, 6-stoxycarbanyl-M4-(ethoxycarbonylmethyl)-ethoxycarbonylmethyleneoxyphenyl)-5- 142 -(4-thoxycarbonylmethyleneoxyphenyl)-5-nitro-2,4-ptyrimylindiamine is obtained in nitro-72,4-pyrimidinediamine (К925858) as a result of the reaction of M-(2-chloro-b-ethoxycarbonyl. 5-nitro-4-pyrimidinyl)slicineethyl ether and ethyl 4-aminophenoxyacetate. IN NMR (SOSIS): 20 9.00 (Bb5, 1H)), 7.49 (05, 1), 7.41 (9, 2H, 1- 9.0 Gy), 6.89 (0, 2H, 1-90

Gi), 4.62 (5, 2H), 4.46 (a, 2H, 3-:7.2 Hz), 4.31-4.19 (t, 6), 1.40 (6 ZN, 3 : 7.2 Gy), 1.33-1.25 (t, 5H); LC/MS: retention time: 30.00 minutes; purity: 98 95;

MC (mass/charge): 492 (MN). 7.3.441 Ma-benzyloxy-5-stoxycarbonyl-M2- Analogously to the preparation of M4-(3,4-ethylene lyoxyphenyl)-5-fluoro-I42-(3- (C α-ethylenedioxyphenyl)-2,4- hydroxyphenyl)-2, 4-pyrimidinediamine, M4-benzyloxy-5-stoxycarbonyl-im2-(3,4-pyrimidinediamine (5925837) ethylenedioxyphenia)-2,4-pyrimidinediamine is obtained as a result of the reaction of IMa-benzyloxy-2-chloro-5-stoxycarbonyl-4-pyrimidineamine and I.4-benzodioxan-b-amic. IN NMR (0M50-46u: s) 8.55 (5, 1H), 7.49-7.44 (ha, 311), 7.39-7.34 (t, 411), 7.30-7, 22 (t, IN), 6.657 (4, 1H, 1- 84 Gy)), 4.98 (5, 28), 4.23-4.17 (t, NI), 1.26 (5 ZA, 1 -7.2 Hu; LC/MS: retention time: 26.4 minutes; purity: 9515; MS s (mass/charge): 423 (MN). - st o 7.3.442 M4-benzyloxy-5-ethoxycarbonyl- M 2-(3- Analogously to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, M4-bexyloxy-5-ethoxycarbonyl -M24(3-(5925824) hydroxyphenyl)-2,4-pyrimidinediamine is obtained from the reaction of M4-benzyloxy-2-chloro-5-ethoxycarbonyl-4-pyrimidinamine and 3-hydroxyaniline. (Te

RHU/MS: retention time: 24.28 minutes; purity: 88 90; MS (mass/charge): 381 (MmNnu. o 7.3.443 142, M4-bis|4- A mixture of 4-nitrophenol (7.65 g, 55 mmol), 2-bromoacetamide (6.90 g, 50 mmol) and (aminocarbonylmethyleneoxy)phenyl|-5- K2СО3 (13.8 g, 0.1 mol) is stirred in acetone (50 ml) at room temperature for 24 hours. The mixture obtained as a result of the reaction - dissolved in water, and the acetone was removed under reduced pressure. The light yellow residue formed was collected by filtration, washed with water, and dried to give 1-aminocarbonylmethyleneoxy-4-nitrobenzene (8.28 g, 8495). (ee)

Hydrogenation of 1-aminocarbonylmethyleneoxy-4-nitrobenzene (3 g, 15 mmol) in methanol (50 mL) catalyzed by 1092 Ra-C (500 mg) and Ma2504 (500 mg) at 3.4 atm for 2 h, leads to the formation of 4-(aminocarbonylmethyleneoxy aniline (2.59 g, quantitative deviation). 4-(aminocarbonylmethyleneoxy)aniline (500 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol ) is dissolved in methanol (10 ml) and water (1 ml) and stirred at room temperature for 24 hours. After that, the methanol - c is removed under reduced pressure. The remaining aqueous solution is acidified with IM HCI (80 ml). The resulting The white residue was collected by filtration to give M2,M4-bis|4-(aminocarbonylmethyleneoxy)phenyl|-5- and fluoro-2,4-pyrimidinediamine (370 mg, 7295). 1H NMR (acetone-d6)y: 7 4 .46 (5, 2H), 4.50 (5, 2), 6.81 (Be, MH, 2H), 6.91 (4, 2- 9.0 Hu, 2), 6.98 (0, 1-90 Hu, 2), 7.20 (be, 2H, MNU, 7.63 (6, 2-93 Gy, 2H), 7.72 (4, 12 8.7 Hz, 7H), 7.93 (y, 1-36 Gy, IN). 8.27 (Bk, IN, MN), 8.44 (g, IN, MN); LC/MS: retention time: 13.91 minutes; purity: 10096; MS (mass/charge): 427.02 (MNK). so 73444 1M2,M4-bisi4-(cnanmethyleneoxy)phenyl!-5- | To a solution of M2,M4-bis4-(aminocarbonylmethyleneoxy)phenyl|-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (K945032) pyrimidinediamine (200 mg, 0.47 mmol) in TF (10 ml) at room temperature trifluoroacetic anhydride (0.33 ml, 2.35 mmol) and pyridine (0.38 ml, 4.7 mmol) were added at room temperature, and the mixture was stirred overnight at room temperature. The resulting mixture is dissolved in ethyl acetate (80 ml) and IM NH! (80 ml).

The organic layer is washed with a solution of 1M NA! (2 x 60 ml), water (2 x 60 ml) and "o 20 brine (60 ml). The ethyl acetate layer is dried and evaporated. Remainder 42)

F) ko 60 b5 was recrystallized from ethyl acetate and hexane to obtain 12, h4-bis|4-(panmethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediamine (159 me, 8795) in the form of a white solid fraction. 1H NAM (acetone-db). P 5.09 (5, 2H), 5.16 (in, 2H), 7.08 (4.1 9.3 Hz, 2NU, 7.17 (a, 12 9.0 Hz, 2, 7.63 (a, 7: 9.0 Hn, 2H), 7.77 (8, 12 9.3

Ha, 2Nu, 8.174, 154.8 Hz, 1), 9.55 (bg, 1Н, МН), 11.00 Сг, IN, МН); RH/MS: 21.47 typ.; 96.1195; MC (mass/charge): 391.20 (MN). 7.3.445 2, Ma-bis(44(1H-1,2,3,4-tetrazole-5- To a solution of IM2,M4-bis(4-(cyanomethyleneoxy)phenyl-5-fluoro-2,4-pyrkmidinediaminyl) )methyleneoxyphenyl|-5-fluoro-2,4- (100 mg, 0.26 mmol) in DMF (10 mL) overcome MNACI (136 mg, 2.54 mmol), pyrimidinediamine azide (5945033) sodium (100 mg, 1 .54 mmol) and one drop of acetic acid, after which the resulting solution is left to stir at a temperature of 702C overnight. Next, this solution is titrated with ethyl acetate (80 ml) with the formation of a precipitate. This precipitate is collected by filtration, washed with a solvent M 70 NOI and water to obtain M2,IM4-bis/4-(1H-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl|-5-fluoro-2,4-pyrimidinedisamine (66 mg, 5420) in in the form of a white solid fraction. IN NMR (SPZOII2): HI 5.31 (5, 2H), 5.34 (z, 2H), 6.93 (d, 1- 9.0 g, 2), 7.00 (y, 32: 9.3 Hz, 2), 7.04 (y, 1-2: 9.0 Hz, 2, 7.57 (b, 12 9.0 Go, 28), 7.81 (а4 ,3- 4.2 Ha, 18); LC/MS: 16.54 minutes; purity: 88.34; MS (mass/charge): 477.02 (MN). 7.3.A46 M2,Ma-bis(4 -methoxycarbonylphene yl)-5- A mixture of 4-aminobenzoic acid (410 mg, 3 mmol) and fluoropyrimidine 2,4-dichloro-5-fluoro-2,4-pyrimidinediamine (945034) (100 me, 0.6 mmol) was stirred in methanol ( 10 ml) and water (1 ml) at a temperature of 1002C for 24 hours to obtain M2,M4-bis(4-carboxyphenia)-5-fluoro-2,4-pyrimidinedismine, after which methanol is removed.

The precipitate formed is redissolved in DMF (10 mL), potassium carbonate (1.65 t, 12 mmol) and iodomethane (0.37 mL, 5 mmol) are added, the resulting mixture is stirred at room temperature overnight, and then dissolved with 1M

NS! (50 ml) and ethyl acetate (80 ml). The stylacetate layer is washed with IM solution

NS! (60 ml) and water (60 ml). The organic layer was separated, dried, evaporated and the precipitate formed was recrystallized from ethyl acetate/hexane to give I42,M4-bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (150 mg, 6395). IN NMR Gaceton-db): C! 3.85 (in, ZN), 3.88 (5, ZN), 7.88-7.97 (t, 4H), 7.98-8.05 (t 48), 8.18 (y, 7 - 3.0 Hz, EN), 9.00 (bt, 1H, MA), 9.04 (Be, IN, MH); RF/MS: retention time: 27.07 minutes; purity: 95.5405; MS (mass/mass): 397.04 (Mn. 7.3.447 2, M4-bis(3-methoxycarbonylphenyl)-5» Analogously to the preparation of M2,M4-bis(4-methoxycarbonylphenyl)-5-fluoro-2,4- Sem fluoro-2,4-pyrimidinediamine (K945035) pyrimidinediamine, M2,M4-bis(3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (180 mg, 7695) is obtained in the form of a white solid fraction as a result of ) reactions of 3-aminobenzoic acid (410 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimiline (100 mg, 0.6 mmol). 1H NMR (acetone-46): О 3.81 (z, ZNI), 3.83 (5,

ZN), 7.37 (672 8 Hz, SN), 7.47 (1-81 Gy, NU, 7.60 (a, 12 7.8 Ha, 1), 7.75 (y, 3 7.5 Go, 1H), 8.02 (4, 72 6.3 Hz, IN), 8.10 (4, 7- 3.6 Hz, 11), 8.24 (d, 7: 8.4 Hz, 18 ), 8.36 (4, 12 11.4 Go, 2H), 8.74 (bg, 1H, МН), 8.82 (g, IN, МН); РХ/MS: duration (Се) of retention: 22 .77 minutes; purity: 91.0475; MS (mass/charge): 397.00 (M). 7.3.448 M2,ma-bis(3-carboxyphenyl)-5-fluoro-2,4- | Solution M2, MA-bis(3-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (100 mg, (2) pyrimidinediamine (K945036) 0.25 mmol) and Masn (149 mg, 3.5 mmol) are stirred in a mixture of TI F :H 2 O (5 mL of each solvent) at room temperature overnight.The reaction mixture was dissolved in water (60 mL) and ethyl acetate (60 mL).

The aqueous layer is separated and acidified with calculated 1M HCl to pH 3. p

The formed precipitate is collected by filtration and recrystallized from methanol to obtain M2,M4-bis(3-carboxyphenia)y 5-fluoro-2,4-

From pyrimidinediamine (54 mg, 5825) in the form of a white solid fraction. IN NMR ge) (SRPZOB): 07.31 8.1 Hz, 1), 7.42 (3-8, Go, 1NU, 7.61 (dit, 1- 7.8 Hz, 1H), 7.76 (dz , 2-84 Hz, 1), 7.89 (dt, 3- 7.2 Gu, KN), 7.98 (4, 7- 3.6 Hz, IB), 8.01 (t, 1H), 8.20 (t, 1H)), 8.37 (z, IN); ЭХ/МС: the duration of the gathering: 15.77 minutes; purity: 98.8495; MC (mass/charge): 369.03 (MN). 7.3.449 M2,M4 bis(4-carboxyphenyl)-5-fluoro-2,4-. | Similarly to the preparation of М2,М4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (29450373 pyrimidinediamine, М2,144-bis(4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (55 mg , 5999) are obtained in the form of a white solid substance as a result of the reaction of

M2,ma-bis(4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (100 mg, 0.25 s mmol) and MaOH (200 mg, s mmol). IN NMR(SPZOB): 2 7.77 (d, 1- 8.7 Hz, 2H), and 7.92 (4, 3- 8.7 Gy, 2NU, 7.94 (0, 1-- 8.4 Hz . : 10095; MS (mass/charge): 368.87 (MNK). 7.3.450 M2,MA-bis(3- M2,ma4-bis(3-isopropylaminocarbonyloxyphenyl)-5-fluoro-2,4-pyrimidineliamine isopropylaminocarbonyloxyphenyl) -5- is obtained as a result of the reaction of 1 equivalent of M2,M4-bis(3-hydroxyphenia)-5-fluoro-fluoro-2,4-pyrimidinediamine (К926412) with 2,4-pyrimidinedimine and 3 equivalents of isopropylisocyanate in the presence of pyridine in SNOIS2 at at room temperature for 24 hours followed by extraction using CH 2 Cl 2. 1H NMR (SOSIS - SOSOIO): C 7.82 (9.18, co 1-3.6 Hz), 7.66 (Ba, IN), 7.48 , 1 Nu. 7.15-7.02 (t, 2H), 6.76-6.76 (t, 2H), 6.56 (а, 1H, 1-81 Hz), 6.45 (ad, 1H, 3 1.8 and 8.4 Hz), 4.70 (t, 2H), 1.05 (9, 12, 3- 6.3 sho Hz 192 NMR (SOSIZ - SOZO0uU -27206; VK/MS: retention time: 15.40 minutes, purity: 9095. ---------......2..:ЙЙ.Й.: 2ЙЙ.:2ЦЮ8ЮЭ8:ЦВ:8ЙЙ:Ц8Ц8ВШЦЗЧКЙЙЙЙЕНИНIVЦТУТНЦЮЮ (Se) 42) ko 60 b5

7-3.451 M2,M4-bis|4- A mixture of 1,4-diaminobenzene (4 g, 37 mmol), ethyl isoisomanate (1 ml, 12.6 mmol) and (stylaminocarbonylamine)phenyl|-5-fluoro- | of potassium carbonate (8.72 g, 53 mmol) was stirred in THF (20 mL) at room temperature 2,4-pyrimidinediamine (K945040) overnight. The mixture obtained as a result of the reaction is separated in a solution of IM NOSI (80 ml) and ethyl acetate (80 ml). The aqueous layer was extracted with ethyl acetate (4 x 80 ml). The combined organic layers were dried, evaporated, and recrystallized from MEOH/CH2OCI2/hexane to afford 4-(stylaminocarbonylamino)aniline (1.4 g, 6292) as a beige solid fraction.

Similarly to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, M2,M4-bis|4-(ethylaminocarbonylamino)phenyl-5-fluoro-2,4-pyrimidinediamine (180 mg, 6675 ) are obtained as a result of the reaction of 4-(ethylaminocarbonylamino)aniline (537 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol). IN NMR (SOSO): 1.16 (i, 2-7.2 Hz, EN), 3.24 (9, 2-7.2 Hz, 4H), 7.29 (4, 3- 9.0 Ga , 28), 7.40 (, 29.0 Gi, 4H), 7.55 (4, 12: 9.0

Gi, 2), 7.87 (5, IN, MN), 7.89 (5, IN, MN); LC/MS: retention time: 16.93 minutes; purity: 93.4395; MS (mass/mass: 453.03 (MN). 7.3.452 Ma, M4-bisI3- Analogously to the preparation of M2, Ma4-bisi4-(ethylaminocarbonylamino)phenyl)-5-fluoro-(ethylaminocarbonylamino)phenyl|-5- 2, 4-pyrimidinediamine, 3-(ethylaminocarbonylamino)aniline (940 mg, 8396) fluoro-2,4-pyrimidinediamine (K945045) is obtained as a result of the reaction of 1,3-diaminobenzene (2 g, 18.5 mmol), ethyl isocamanate (0 .5 ml, 715 6.3 mmol) and potassium carbonate (4.36 g, 31.5 mmol). M2,M4-bis|3-(ethylaminocarbonylamino)phenyl|-5-fluoro-2,4-pyrimidinediamine (180 mg, 6695) is obtained in the form of a white solid fraction as a result of the reaction of 3-(ethylaminocarbonylamino)aniline (537 mg, C mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 9.6 mmol). IN NMR (SOZOUU; 231.14 (i, 7-6.9 Go, ZN), 115(61-:7.5 Gy, ZNU), 3.21 (4.42 7.2 Hz, 2H), 3 .22 (9, 3- 7.5 Go, Nu, 7.06 (aad, 7- 0.9, 2.1, 7.8 Gu, 1H), 7.10-7.28 (t, 58) . ; purity: 89.6395; MS (mass/charge): 453.38 (MH). 7.3.453 M2,Ma-bis(4-hydroxy-3- Solution M2,Ma-bis(3-carboxy-4-hydroxyphenyl)- 5-Fluoro-2,4-pyrimidinediamine (70 methoxycarbonylphenyl)-5-fluoro-2.4-mi, 0.17 mmol) and thionyl chloride (0.04 ml, 0.55 mmol) were dissolved in MeOH (10 pyrimidinediamine (8945043) ml ) overnight. The methanol is removed by evaporation. The precipitate formed is dissolved

EOAc (60 ml) and sodium bicarbonate solution (60 ml). The VOAS layer is washed with an aqueous solution of MaHSOZ (60 ml) and water (50 ml). The organic layer is dried, evaporated and crystallized to obtain MEON/ESO

M2,M4-bis(4-hydroxy-3-methoxycarboniaphenia)-5-fluoro-2,4-pyrimidinediamine (58 Ge) mg, 77). HNMR (YUM50-46): 77 3.69 (z, ZN), 3.71 (5. ZNO, 6.81 (4, 3-9.3 Hz, 18), 6.92 (a,3 - 9.0 Hz, 1), 7.64 (ad, 1- 2.7; 9.0 Gy, IN), 7.84 (44.32 2, and 84 Gy, 1 NU, 8.03-8.07 ( t, 3 H), 9.14 (5, 1 H, MH), 9.34 (5, 1 H, MH), 10.16 (5, and H, OH), 10.29 (5,

IN, ON); 19E NMR (282 MGy, BM5O-y6): 7 -165.60; РХ/MS: duration (Хе) of retention; 22.24 minutes; purity: 10095; MS (mass/charge): 428.98 (MI). 7.3.454 M, Ma-bisg4-(2-methyl-1,2,3,4-hetrazol-5- | Compound M2,144-bis4401 H-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl )-5-fluoro-2,4-(e»)yl)methyleneoxyphenyl|-5-fluoro-2,4-pyrimidinediamine (30 mg, 0.063 mmol), iodomethane (0.024 mL, 0.38 mmol) and pyrimidinediamine (k945046 ) K2CO3 (88 mg, 0.64 mmol) was stirred in DMF (5 mL) at room temperature overnight. Next, this compound is diluted with ethyl acetate (50 mL)

With fluorine MK methi Gal, 2 and water (50 ml). The organic layer is washed with water (50 ml) and brine (50 tetravol-v-yl)umethyleneoxyphenyl 4 ml). After separation, this layer of ethyl acetate is dried, evaporated and purified in three steps using column flap chromatography (EEODs/hexane - 2/1, 1/1, ЕУ As) with il methyleneoxyphene 0 7 in order to obtain the sum of the following compounds: M2, ch4-Obisi4-(2-methyl-1,2,3,4-s pyrimidinedimine ( ) tetrazol-5-yl)methyleneoxyphenyl|-5-fluoro-2,4-nyrimidinediamine KU45046 (6 mg,

Mo, ma-bis(4-(1-methyl-1,2,3,4-tetrazop-5- | 1995), IN NMR (SOSIS): 2 4.37 (5, ZN), 4.38 (5 . .76 (5, 1H), 6.98 (0.3-9.0 Hz, 28), 7.04 (a, 1-93 Hz, 2H), 7.42 pyrimidinediamine (K945048) (d, 159, 0 Hz, 2), 7.51 (y, 7: 9.0 Go, 2H), 7.90 (bt, 1H); 192 NMR (282 MHz, SOSIZ): 01 -168.52; LC/MS: retention time: 20.44 minutes; purity: 94.9295; MS (mass/charge): 505.02 (MN); 5-fluoro-M2,Ma4-14-(1-methyl-1,2,3,4-tetrazole-5-" ilumethyleneoxyphenyl,(4-(2-methyl-1,2,3,4-tetrazop-5- yl)umethyleneoxyphenium|-2,4- pyrimidinediamine K945047 (8 me, 2595), INT NMR (SOS): С 4.18 (5, ЗН), 4.29 (5, ssh

ZN), 4.36 (5, ZN), 4.37 (5, ZNI), 5.34 (5, 2H), 5.37 (in, 2H), 5.42 (5, 2), 5, 46 (5, 2H), s 6.69 (u, 2H), 6.80 (5, 1), 6.83 (5, 14), 6.91 (0, 2- 9.3 Hz, 2) , 6.98 (y, 1- 9.0 Hz, and 2), 6.99 (0, 22 9.3 Hz, 2), 7.04 (4, 159.0 Hz, 2), 7.41 (y, 7: 9.9 Hn, 2H), 7.44 (y, y - 129.3 Gy, 2NU, 7.50 (0, 1- 9.0 Sy, 2H), 7.54 (a, 3: 9.0 Hz, 2H), 7.91 (Lg, 2NU; 19

NMR (282 Mn, SOSISU: 7 -168.39, -168.16; LC/MS: retention time: 19.42 minutes; purity: 91.1825; MS (mass/charge): 504.99 (MN .k); and M2,M4-bisy4-411-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl)-5-fluoro-7,4-pyrimidinediamine

K945048 (6 mu, 1995), IN NMR (SPZOYU - SOSIZU: 71 4.20 (5, ZN), 4.22 (5, ZN), 5.50

Go! (5.2NU, 5.55 (v, 2H), 6.95 (d, 22 9.0 Gy, 2H), 7.02 (j, 1: 9.3 Hz, 2H), 7.52 (j , 2-: 9.0

Gy, 2H), 7.66 (4, 12: 9.3 Hz, 2), 7.84 (y, 3- 3.6 Hu, 1Hu, and 9E NMR (282 MHz,

SsrzOorSrsizh D) -163.12; LC/MS: retention time: 18.32 minutes; co purity: 83.4195; MS (mass/charge): 504.99 (MN). -y 7.3.455 Ma-(4-aminocarbonylmethyleneoxyphenyl)- | Analogous to the preparation of 2-chloro-1M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-"se 5-fluoro-M2-(4-pyrimidinamine, M4-(4-aminocarbonylmethyleneoxyphenyl)-2-chloro-5-fluoro -4- methoxycarbonylmethyleneoxyphenyl)-2,4- | pyrimidineamine (270 mg, 7695) is obtained as a result of the reaction of 4- (42) ko 60 b5 pyrimidinediamine (K945052) "aminocarbonylmethyleneoxy)aniline (398 mg, 2.4 mmol) and 2,4-dichloro-3-fluoropyrimidine (200 mg, 1.2 mmol). Similarly to the preparation of M2, Ma-bis(3- thydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, MA-(4- aminocarbonylmethyleneoxyphenyl)-3-fluoro-m2-(4- methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (120 mg, 8095) are obtained as a result of resection of methyl 4-aminophenoxyacetate (183 mg, 11 mmol) and Ma4-(4-aminocarbonylmethyleneoxyphenyl)-2-chloro-53-fluoro-4-pyrimidinamine 4100 mg, 0.34 mmol). 1 NMR (adeton-yb): 1 3.25 (5, ZNI), 3.98 (5, 211), 4.33 (5, 2H)U, 6.45 (4, 1- 8.7 Hz, 2H), 6.49 (9.1-9.3 Hz, 2H), 6.93 (y, 1-5 8.7 Hn, 2H), 7.13 (4, 7- 9.0 Gy, 2H), 7.71(4.1-5.1 Gy, 1H), 9.46 (g, IN, MH), 9.78 (im, IN, MH); LC/MS: retention time: 16.65 minutes; purity: 10025; MS (mass/charge): 442.01 (MN). 7.3.256 Ma-(4-cnanomethyleneoxyphenyl))5-fluoro-| Similar to the preparation of M2,M4-bis(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4-

M2-4. pyrimidinelismin, M4-(4-cyanomethyleneoxyphenyl)-5-fluoro-M2-(4- 7170 methoxycarbovylmethyleneoxyphenyl)-2,4- | methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (52. mg, 6895) is obtained in the form of pyrimidinediamine (5945053) in the form of a white solid fraction as a result of the reaction M4-(4-aminocarbonylmethyleneoxyphenia)-5-fluoro-142-(4-methoxycarbonylmethyleneoxyphenyl)- 2,4-pyrimidinediamine (80 mg, 0.18 mmol), trifluoroacetic anhydride (0.13 mL, 0.92 mmol), and pyridine (0.15 mL, 1.84 mmol). IN NMR (YUM50-46): 1 3.24 (5, ZNI), 4.26 (5, 2H), 4.71 (5, 21), 6.36 (d, 1-93 Go, 2H), 6.59 (4, 1-2 9.0 Hz, 2H), 7.06 (0, 2: 9.0 Hn, 2NU, 7.28 (y, 1-9.0 Hz, 211U, 7.58 (0 ,2 3.6 Hz, 18), 8.59 (lh, IN,

MH), 8.85 (Bg, 1H, MH); 19E NMR (282 MHz, OM50-abu: Pi -166.26; LC/MS: retention time: 21.37 minutes; purity: 10095; MS (mass/charge): 424.01 (MN. 7.3.457 M2, MA-bis|3-hydroxy-4- A solution of 4-amino-2-hydroxybenzoic acid (1 g, 6.5 mmol) in MEON (15 mL) and (methoxycarbonyl)phenyto-5-fluoro-2,4-concentrated sulfonic acid ( 1 ml) is refluxed overnight. Pyrimidinediamine (8945056) The mixture obtained as a result of the reaction is rapidly cooled using an aqueous solution of NaHCO3 (60 ml) and ЕУАс (60 ml). The organic layer is separated, dried and evaporated in order to retain 3-hydroxy-4 - methoxycarbonylaniline.

Similarly to the preparation of M2,MA-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, M2,MA-bis-|3-hydroxy-4-(methoxycarbonyl)phenyl|-5-fluoro-2,4- tyrimidinediamine (105 mg, 4195) is obtained as a result of the reaction of 3-hydroxy-4-methoxycarbonylaniline (500 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (1600 mg, 0.6 mmol). 1H NMR (YUM5O0-46): Г: 3.90 (5, 3), 3.93 (5, 3), 7.31 (7-24; 9.0 Gy, 1H), 7.56 (44, 1 2.1; 8.7 Hz, 1H), 7.63 (8.221 Hz, 1H), 7.67 (4, 2-7, Si, Ha! in IN). 7.67 (4, 12 9.0 Hz, IN). 7.79 (4, 1-90 Gy, 18), 8.28 (4, 1-5.6 Hn, 1H), 9.72 (5,

IN, MH), 9.825, 1H, MH), 10.77 (5, IN, OH), 10.80 (5, IN, OH); 192 NMR (282 MHz, approx

ОМ50-45): 0 161.74; LC/MS: retention time: 31.47 minutes; purity: 96.0395; MC (weight/weight): 428.99 (MNK). 7.3.A58 M2-(4-aminocarbonylmethyleneoxyphenyl)- | Analogous to the preparation of M4-(4-aminocarbonylmethyleneoxyphenyl)-3-fluoro-ich2-(4-5-fluoro-ich4-(4. methoxycarbonylmethylene oxyphenyl)-2,4-pyrimidineliamine, IM2-(4- se methoxycarbonylmethyleneoxyphenyl)-2,4 - | aminocarbonylmethyleneoxyphenyl)-3-fluoro-M4-(4-methoxycarbonylmethylene pyrimidinediamine (2945060) oxyphenyl)-2,4-pyrimidinediamine (145 mg, 6895) restrain the resulting reactive 2-chloro-5-fluoro-M4-(4- methoxycarbonylmethyleneoxyphenyl)-4-pyrimidinamine (150 mg, b» 0.48 mmol) and 4-(aminocarbonylmethyleneoxy aniline (240 mg, 1.44 mmol). IN

YAM (0М50-46У: З) 3.70 (5, ZN), 4.40 (5, NU, 4.81 (5, 2), 6.91 (d, 15 8.4 Hz, 2 H), or 6 .93 (4, 1: 8.4 Gu, 211), 7.36 (d, 7-: 8.4 Gy, 2NI), 7.54 (0, Ge 8.7 Ho, 2H), 8.21 (4, 2-48

Hz, 1H), 10.13 (be, IN, MH), 10.39 (Be, IN, MH); 19E NMR (282 MHz, OM5O-46X: 0 - se 162.26; LC/MS: retention time: 15.37 minutes; purity: 78.4995; MS (mass/charge): 442.07 (MH). s 7.3.459 M2,Ma-bis(3-hydroxy-4-carboxyphenyl)- Similar to the preparation of M7,M4-bis(3-carboxyphenyl)-z-fluoro-2,4-5-fluoro-2,4-pyrimidinediamine (K945061 ) of pyrimidineliamine, M2,M4-bis(3-hydroxy-4-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine (50 mg, 7795) is obtained in the form of a white solid fraction as a result of the reaction of M2,M4-bis3-hydroxy -d-(methoxycarbonyl)phenyl|-5-fluoro-2,4-pyrimidinediamine (70 mg, 0.16 mmol) and MAON (100 mg, 2.5 mmol). .23 (49, 7: 1.5 and 8.7 Hz, 1H), 7.46-7.52 (t, ЗН), 7.63 (0.412 5.7 Hz, 1H), 7.72(4 ,1-8.7 Hz, 1H), 8.28 (8, 1- 3.3 Hz, 1), 9.71 (5, IN, MNU, 9.795, IN,

MH), 11.34 (bg, 2NU; 192 NMR (282 MGy, OM5O-46): 0 -161.10; LC/MS: duration - with retention: 20.76 minutes; purity: 84.65; MS ( mass/charge): 400.95 (MNK). 7-3.460 M2-(4-cyanomethyleneoxyphenyl)-5-fluoro- from Mma-(4.pyrimidinediamine, M2-(4-cyanomethyleneoxyphenyl)-5-fluoro-M4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4- | methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (66 mt, 6999) is obtained pyrimidinediamine (KO45062) in the form of a white solid fraction as a result of the reaction of M2-(4-aminocarbonylmethyleneoxyphenyl)-5-fluoro-M4-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (100 mg, 0.23 mmol),

Go! of trifluoroacetic anhydride (0.16 mL, 1.13 mmol) and pyridine (0.18 mL, 2.21 mmol). IN YAM (acetone-4b): 7. 3.75 (in, ZN)), 4.67 (5, 2H), 4.89 (5, 2H), 6.88 (0, 1- 9.0 Hz , 2H), 6.90 (4, 3-93 Hz, 2H), 7.48 (y, /- 9.0 Gu, 2H), 7.54 (y, 7: 9.0 Hz, 28),

Kkz 7.54 (a, 1-42 Hz, 18), 9.17 (bg, 1H, MH), 10.59 y, 1H, MH); 192 NMR (282 MGy, acetone-de): GI -154.65; LC/MS: retention time: 20.69 minutes; purity: shk 94.3592; MC (mass/charge: 424.02 (MN (Ce) 42) ko 60 b5

7.3.451 M2,Ma-bis(3-methoxy-4- Similar to the preparation of M2144-bis/4-(2-methyl-1,2,3,4-tetrazole-5-methoxycarbonylphenyl)-5-fluoro-2,4 - yl)methyleneoxyphenyl|-5-fluoro-2,4-pyrimidinediamine, methyl-2-methoxy-4. Pyrimidinediamine (K945065) nitrobenzoate (820 mg, 7725) is obtained in the form of a solid white fraction as a result of the reaction of 2-methoxy-4-nitrobenzoic acid (1 g, 5 mmol), potassium carbonate (1.4 g, 10 mmol) and iodomethane (0.47 ml, 7.5 mmol). 9 Methyl 4-amico-2-methoxybenzoate (600 mg, quantitative) is formed by the hydrogenation of methyl 2-methoxy-4-nitrobenzoate (700 mg, 3.3 mmol) in methanol (10 mL), catalyzed by 592 P4-C (100 mg) and Ma2504 (100 mg) at a pressure of 3.4 atm for 1 hour.

Similarly to the preparation of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, M2,M4-bis(3-methoxy-4-methoxycarbonylpheny)-5-fluoro-2,4- 70 pyrimidinediamine (180 mg, 6695) is obtained in the form of a white solid fraction as a result of the reaction of methyl-4-amino-2-methoxybenzoate (542 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol). IN YAM (acetovn-db): O 3.76 (5,

ZN), 3.77 (5, ZNU, 3.81 (5, 6H), 7.36 (ad, 3-1.8; 8.7 Gi, 18), 7.57 (5, IN", 7 .58 (44, 7- 2.1 and 7.2 Hz, 1H), 7.69 (4, 152.1 Hz, 1H), 7.73 (4, 5- 8.4 Gy, 1NU, 7.754, 1- 9.0 Hz,

IN), 8.17 (а, - 3.3 Hz, 1Н)), 8.89 (в, 2Н, МН); 192 NMR (282 MHz, aypetonedb): I - 165.18; LC/MS: retention time: 23.17 minutes; purity: 10095; MS (mass/charge): 456.96 (MN V). 7.3.462 M2,M4-bis(4-methoxy-3- Similar to the preparation of M2,m4-bis(3-methoxy-4-methoxycarbonyl)pheny)-5-fluoro-methoxycarbonylphenyl)-5-fluoro-2,4- 2 ,4-pyrimidinediamine, methyl 2-hydroxy-5-nitrobenzoate (880 mg, 7799) is obtained in pyrimidinediamine (K945066) as a result of the reaction of 2-hydroxy-5-nitrobenzoic acid (1 g, 5.5 mmol), potassium carbonate (3 g, 22 mmol) and iodomethane (1 ml, 16 mmol).

Hydrogenation of methyl 2-hydroxy-5-nitrobenzoate (700 mg, 3.3 mmol) using 1095 Ra-C (100 mg) and Ma2504 (100 mg) in MEeOH at a pressure of 3.4 atm allowed the formation of methyl- of 5-amino-2-methoxybenzoate (600 me).

Similarly to the preparation of M2,M4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine,

M2,M44-bis(4-methoxy-3-methoxycarbonylphenyl)-5"fluoro-2,4-pyrimidinediamine (1790 me, 6295) is obtained in the form of a pink solid fraction as a result of the reaction of methyl-5-amino-2-methoxybenzoate (542 mg, 3 mmol) and 2,4-dichloro-5" fluoropyrimidine (100 mg, 0.6 mmol). 14 NMR (acetone-db): 0 3.76 (z, ZN), 3.77 (6,

ZN). 3.88 (5, ZNU, 3.93 (5, ZN), 7.08 (ai, 4-0.8; 9.0 Hz, IN), 7.18 (0, 1: 9.0 Gy, IN, 7, 56 (44, 1- 3.0 and 8.7 Go, 1), 7.78 (44, 1- 1.5 and 3.0 Gy, INU, 7.86 (91, 7- 2.7 and 9 ,0 s

Hz, EN), 7.98.3: 2.7 Hz, 1H), 8.32 (4, 12 5.1 Hn, 1H); 19E NAM (282 MHz, acetone-h6u: -163.88; LC/MS: retention time: 19.07 minutes; purity: 98.1795; MS Ge)

Ш0ШЗШБЗ-О0Б0-ООО-502000000000001 p oceans 700027 7.3.463 M2,M4-bis(3-carboxy-4-methoxyphenyl)-5- | Similarly to the preparation of M2,44-6bis(3-carboxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (K9U45067) pyrimidinediamine, M2,Ch4-bis(3-carboxy-4-methoxyphenyl)-5- fluoro-2,4-pyrimidinediamine (80 mg) is obtained as a result of the reaction of M2.44-bis|4-methoxy-3-(se) (methoxycarbonyl)phenyl|-5-fluoro-2,4-pyrimidinediamine (80 mg, 0 .15 mmol) and

Mahon (200 mg, 5 mmol). IN YMR (OM 5O-a6): And! 3.75 (5, ZN), 3.80 (5, ZN), 6.94 (y, b 1:9.6 Hz, 1H), 7.05 (4, 1-9.5 Hz, TER, 7.78-7.80 (t, ZN), 7.94 (ad, 1: 9.3 Gy, IN), 8.04 (a, 7-36 Hz, 18), 9.10 (5, 1NI , MH), 9.30 (5, 1H, MH); 192 NMR (282 MHz, pPM5O-46); 1,165.56; LC/MS: retention time: 14.65 minutes; purity: h 10095; mass/charge): 428.83 (MIN). 7.3.464 M2,M4-bis(4-carboxy-3-methoxyphenyl)-5- | Similar to the preparation of M2,M4-bis(3-carboxyphenyl)-5-fluoro- 2,4-se fluoro-2,4-nirvmidinediamine (K945068) of pyrimidinediamine, M2,M4-bis(4-carboxy-3-methoxyphenia)-5-fluoro-2,4-3 pyrimidinediamine (18 mg, 6495) is obtained in in the form of a white solid fraction (he) as a result of the reaction of M2144-bis(3-methoxy-4-methoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine (30 mg, 0.06 mmol) and MaOH (200 mg, 5 mmol). 1H NMR (rmB5o-aib): С 3.66 (5, ЗН), 3.73 (5, ЗН), 7.37 (4, 1: 8.4 Hz, 1Н), 7.47 (5, 1Н ), 7.49 (z, 1), 7.61-7.71 (t, ZN), 8.25 (0, 1 3.6 Hz, IN), 9.65 (5, IN, MN), 9.70 (5, IN, MN); 19E NMR (282 MHz, OM5O-46); 17 -162.11; LC/MS: retention time: 17.25 minutes; purity: 10072; MS (mass/charge): 429.04 (MN.Yu). 7.3.465 M244-pnanomethyleneoxyphenyl)-5-fluoro- Similar to the preparation of M2,M4-bis(4-cnanomethyleneoxyphenyl)-5-fluoro-2,4- shsh

M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(4-cnanomethyleneoxyphenyl)-5-fluoro-IM4-(3-hydroxyphenyl)- with pyrimidinediamine (K9450701 2,4-pyrimidinediamine (30 mg, 5395) restrain as a result of the reaction of M2-(4- and (aminocarboniummethyleneoxyphenyl)-5-fluoro-M4-(3-hydroxyphenyl)-2,4- and -pyrimidinediamine (60 mg, 0.16 mmol), trifluoroacetic anhydride (0.11 ml, . ,4 and 8.1 Hz, 18), 7.02 (4, 2-9.3 Gu, 201), 7.15 3: 51 Hn, 1NU, 731 (484.3 1.2, 2.1 and 8.1 Ge, 1H), 7.38 (3-52, Hz, 15, 7.78 (4.3- 9.3 Go, 2H), 7.98 (d, 1-3, Hn, IN) , 8.34 (5, IN, MH), 8.42 (5, IN, MH); 192 NMR (282 MG, acetone-db):

Go | s -168.06; LC/MS: retention time: 18.17 minutes; purity: 97.4795; MS (mass/charge): 352.05 (MNK). ko 7.3.466 14-(4-cyanomethyleneoxyphenyl)-M2-443,4- | Similarly to the preparation of 142,44-bi(4-cyanomethyleneoxyphenyl)-5-fluoro-2,4- ethylenedioxyphenia)-5-fluoro-2,4-pyrimidinediamine, M4-(4-cyanomethyleneoxyphenia), M2-4(3,4- ethylenedioxyphenyl)-5" sho pyrimidinediamic (K945172) fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M4A-4-aminocarbonylmethyleneoxyphenyl)-ych2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine, trifluoroacetic anhydride and pyridine in THF. IN'YAMR (Se) 42) ko 60 b5

(SRSIZU: 114.27 (t, 4H), 4.82 (8, 7H), 6.704, 1- 2.4 and 8.4 Hz, IN), 6.759, 2-24

Hz, 1H), 6.86 (y, 1-5 8.4 Gy, 1H), 7.02 (a, 359.0 Hz, 2), 7.32 (a, 29.0 Gy, 2H), 8.64 49.15 1.8 Hu, 1H); 19E NMR (282 MHz, SOSIZ): C -135.58; LC/MS: retention time: 19.92 minutes; purity: 98.0295; MC (mass/charge): 393.98 (MN). 7.3.467 Mm2,ma4-bis|4-|2-methoxyimin-ma ma-bis(4-pnanomethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (50 mg, 013 (amino)stylenoxy|phenyl|-5- fluorine-2.4-mmol), methoxyamine salt NH (54 mg, 0.65 mmol) and sodium bicarbonate (54 mg, tyrimidinediamine (K945096) 0.65 mmol) are dissolved in methanol (5 ml). The solution obtained as a result of the reaction is washed at a temperature of 702C for 7 days. After that, the methanol is removed under reduced pressure, and the mixture is partitioned between EtOAc (60 mL) and water (50 mL). The ethyl acetate layer was washed with water (2 x 60 ml), dried, evaporated and purified by flash column chromatography (EPOdsi/hexane; 1:41; EtOAc) in order to obtain M2,M4-bis|4-|2-methoxynmine- ( amino-) ethyleneoxy|phenyl|-5-Fluoro-2,4-pyrmidinediamine (30 mg, 4892). 1H.NMR (acetone-db): H 3.70 (5, ЗН), 3.71 (5, ЗН), 4.44 (in, 2NI), 4.49 (5, 2Н), 5.43 ( ie, 2H), 5.47 (g, 2H), 6.93 (4, 1- 9.0 Go, 2NU, 7.00 (4, 3-:9.0 Hz, 2NU, 7.62.« a, 1- 9.0 Hz, 28), 7.71 (4.1- 9.0 Gy, 2H), 7.93 (j, 1-- 3.6 Gy, 1H), 8.26 (Bg, IN, MH ), 8.40 (g, IN, MN); 197

NMR (282 MG, acetone-db): GI -169.08; LC/MS: retention time: 14.41 minutes; purity: 10092; MS (mass/charge): 484.97 (MIN-K). 7.3.468 m2-4-carboxymethyleneoxyphenyl)- Ma. Similarly to the preparation of M2,M4-bis(Z-carboxyphenia)-5-fluoro-2,4- (4-cyanomethyleneoxyphenyl)-5-fluoro-2.4- | pyrimidinediamine, M2-(4-carboxymethyleneoxyphenyl)-M4-(4-pyrimidinediamine (К945097) cyanomethyphenoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (5 mg, 5299) is obtained in the form of a white solid fraction as a result of the reaction M4-( 4-cyanomethyleneoxyphenyl)-5-fluoro-M2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamic (10 mg, 0.024 mmol) and ION (2 mg, 9.045 mmol). IN NMR (COSO): Z 4.60 (5, 2H), 4.99 (5, NU, 6.88 (0, 7: 9.0 Hz, 2H), 7.02 (4.22 9.0 Gy, 28), 7.39 (0.32: 8.7 Hz, 211), 7.65 (y, 1- 9.0 Hz, 2H). 7.84 (d, 1: 3.9 Go, 1H)); 19E YM (282

MHz, SOZOP): Gi -168.81; LC/MS: retention time: 17.95 minutes; purity: 86.0495; MC (mass/charge): 409.99 (MN). 7.3.469 5-fluoro-M4-(3-hydroxyphenyl)-M2-(3-(5-) A mixture of 3-nitrophenol (4 g, 29 mmol), bromoketonitrile (2.5 ml, 36 mmol) and methyl-1,2, 4-oxadiazole-3-K2CO3 (8 g, 58 mmol) was stirred in acetone (20 mL) at room temperature with yl)methyleneoxyphenyl)-2,4- overnight. The mixture formed as a result of the reaction is diluted with water (80 ml), pyrimidinediamine (K945127) and acetone under reduced pressure. The pale yellow residue is collected by filtration, washed with water and dried to obtain 1-cyanomethyleneoxy-3-nitrobenzene. family

ШЙ i-cyanomethyleneoxy-3-nitrobenzene (2 g, 11 mmol) is dissolved in methanol (20 mL) (5) and the hydroxyamine salt NH (1 g, 14 mmol) and triethylamine (3 mL, 22 mmol) are added to the resulting solution. The mixture formed as a result of the reaction is heated in a reflux flask for 72 hours, after which the solvent is removed under reduced pressure. The residue is redissolved in THF (30 ml). Acetypic chloride (4 ml, 36 mmol) and pyridine (9 ml, (Te) are added to the resulting solution

OLI toi). The resulting reaction mixture is stirred at room temperature overnight, after which TIF (10 ml), ox (19 ml) and

Mahon (3 g, 75 mmol). The reaction solution is refluxed overnight and diluted (22) with water (80 ml). The aqueous solution is extracted with EtOAc (3 x 60 ml).

After separation, the combined layers of ETO Ac are dried and evaporated in order to obtain 14(5-methyl-1,2,4-oxadiazop-3-yl)methyleneoxy-3Z-nitrobenzene, 1-(5-methyl-1, 2,4-oxadiazol-3-yl)methyleneoxy-3-nitrobenzene was dissolved in THF (10 mL) and water (10 mL) and sodium bisulfite (1 g, 5.7 mmol) and bicarbonate were added.

ZB sodium (1 7, 12 mmol). The resulting mixture was stirred at room (ee) temperature for 30 minutes, then diluted with BOAc (80 mL) and water (80 mL). The aqueous solution is extracted with EtOAc (80 ml). The organic layers were combined, dried and evaporated to give 3-(5-methyl-1,2,4-oxadiazol-3-yl)umethyleneoxyaniline (500 mg, 2295 in four steps). 5-fluoro-M4-(3-hydroxyphenyl)-M2-13-(5-methyl-1,2,4-oxadiazol-3-yl)methylhexoxyphenyl)|-2,4-pyrimidinediamine (35mg, 5192) is obtained in as a result of the reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimyldynamin (40 mg, 0.17 mmol) shsh and 3-(5-methnea-1,2,4-oxadiazole-3-1l ) methyleneoxyaniline (102 mg, 0.50 mmol), IR with NMR (SOSIZU 2.61 (8, ЗН), 5.09 (5, 2Н), 6.58-6.62 (t, 28), 6, 76 (0042: 1.2, 8.1 Gu, 10), 6.84 (y, 2- 1.2 and 7.8 Gy, 1H), 6.92 (y, 12: 3.0 Hz, IN ), 7.139 y, 728.1 Hz, 1H), in! z" 7145412 81 Sn, 1), 7.25 (m, 18), 7.54 (a, 3-2.1; 8.7 Hz, 28), 7.88 (9, 32 3.3 Hz, Institute of National Science and Technology; 19E NMR (282 MHz, SOSIZ); -166.52; LC/MS: retention time: 19.33 minutes; purity: 84.80; MS (mass/mass): 409.35 (MNK). 7.3 .A70 5-fluoro-M2-(3-hydroxyphenyl)-M4-13-(3-I-methoxycarbonylmethyleneoxy-3-nitrobenzene (2 g, 9.5 mmol) is dissolved in THF methyl-1,2,4-oxadiazole- z- (10 ml) and vola (10 ml). MaOn (1 g, 25 mmol) is added to the resulting solution. (ee) yl)methyleneoxyphenyl-2,4- The mixture obtained as a result of the reaction is stirred at room temperature pyrimidinediamine (K945130) overnight, then diluted with water (50 mL) and ECOAc (60 mL).After co-extraction, the aqueous layer was separated and acidified with IM HCl to

pH Z. The resulting white precipitate is collected by filtration, washed with water and dried to obtain 1- - carboxymethyleneoxy-3-nitrobenzene. "about 20 Acetonitrile (2.25 ml, 13 mmol) is dissolved in methanol (10 ml) and added 42)

F) ko 60 b5 hydroxyamine salt NOSI (2 g, 29 mmol) and triethylamine (8 ml, 57 mmol).

The mixture obtained as a result of the reaction is heated in a reflux flask for 2 days, after which the solvent is removed under reduced pressure to obtain acetamidoxime in the form of a white solid fraction.

Acetamidoxime (0.75 g, 10 mmol), 1-carboxymethyleneoxy-3-nitrobenzene (1 g, 5 mmol), 1-(3-dimethylaminopropyl)-3-sylcarboi copper hydrochloride BOS NH (1.45 g, 7.5 mmol) and diisopropylethylamine (2.65 mL, 15 mmol) were dissolved in THF (15 mL) and heated in a reflux flask for 4 h. The mixture obtained as a result of the reaction is diluted with EKO Ac (60 ml) and water (60 ml). Layer

ES is washed with an aqueous solution of sodium bicarbonate (2 x 60 ml), IM NS (2 x 60 ml) and water (60 ml). After separation, the EIOAc layer is dried and evaporated to obtain 1-(3-methyl-1,2,4-oxadiazole-5-1l)methylenoxy-3-nitrobenzene.

Sodium bisulfite (1.5 g, 8.6 mmol), sodium bicarbonate (1.5 g, 18 mmol) and 14(3-methyl-1,2,4-oxadivzol-5-yl)methyleneoxy-3-nitrobenzene ( 1 g, 4 mmol) dissolve

In THF (15 mL) and water (15 mL). The resulting solution was stirred at room temperature for 20 minutes, then diluted with EtOAc (60 mL) and water (60 mL). The aqueous solution is extracted with EOAc (2 x 60 ml). The organic layers are combined, dried and evaporated to give 3-(3-methid-1,2,4-oxadiazol-5-yl)methyleneoxyaniline.

Similarly to the preparation of 44-(3,4-ethylenedioxyphenyl)-5-fluoro-IM2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-"MM-13-(3-methyl 1,242 oxadiazole- 5-yl)methyleneoxyphenyl)-4-pyrimidinamine is obtained as a result of the reaction of 3-3-methyl-1,2,4-oxadiazole-5-1l)methyleneoxyaniline (369 mg, 1.8 mmol) and 2,4-pichloro-5 -fluoropyrimidine (150 me, 0.9 mmol). 5-fluoro-M2-(3-hydroxyphenyl)»

Mm4-I3-(3-methyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine (10 mg, 4225) is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-( 3-(3-Methyl-1,2,4-oxadiazod-5-yl)methyleneoxyphenyl|-4-pyrimidinamine (20 mg, 0.06 mmol) and 3-sidroxyaniline (20 mg, 0.18 mmol). 1H NMR (SRSIZ); GI 2.42 (c, ZN), 5.28 (5, 2H), b, 19sada, 1- 0.9; 2.7 and 8.4 Hz, IN), 6.73 (ad , 2: 0.9; 2.7 and 8.4 Hz, IN), 6.81-6.84 (pt, 2H), 6.88 (444, 7- 0.6; 2.1 and 8, 1 Hz, 1H), 7.13 (6, Le 8.1 Gy, IN), 7.26 (32 B

Hy, 1), 7.40 (g, 18), 7.49 35 2 hy, EN), 7.94-7.97 (t, 2H); 19E NMR (282 MHz,

SOSiIZY g-16711; LC/MS: retention time: 18.80 minutes; purity; 920195;

MS (mass/charge): 409.01 (MN). 7347 5-fluoro-MA-(2- Similar preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3- with methoxycarbonylbenzofuran-5-yl)-M2-(3- | hydroxyphenyl)-2, 4-pyrimidinediamine, M4-(2-carboxybenzofuran-5-yl)-5-fluoro-M2-5-methyl-1,2,4-oxadiazole-3-3-(5-methyl-1,2,4-oxadiazole) -3-yl)methyleneoxyphenyl|-2,4-pyrimidinlismine Ge)yl)methyleneoxyphenyl-2,4- is obtained as a result of the reaction M4-(2-carboxybenzofuran-5-ide)-2-chloro-5-fluoro-4-pyrimidinediamine (2945131) pyrimidicnamine (50 mg, 0.16 mmol) and 3-(5-methyl-1,2,4-oxadiazol-3-yl)methyleneoxyaniline (100 mg, 0.49 mmol).

Similarly to the preparation of M2,Ma-bis|4442-methyl-1,2,3,4-tetrazol-5-ic o,ip)methyleneoxyphenyl-5-fluoro-2,4-pyrimidinediamine, 5-fluoro-M4-(2- Methoxycarbonylbenzofuran-5-1l)-M2-|34(5-methyl-1,2,4-oxadiazol-3-b»yl)methyleneoxyphenyl|-2,4-pyrimidinediamine (40 mg, 5095) is obtained as a result of the reaction of Ma4- (2-carboxybenzofuran-5-yl)-5-fluoro-M2-(3-(5-methyl-1,2,4-oxadiazop-3-ch-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, potassium carbonate ( 100 mg, 0.7 mmol) and iodomethane (0.03 mL, 0.5 mmol). 1H NMR (acetone-46): 2 2.63 (z, ZN), 3.94 (z, Ha

ЗН), 5.04 (5, 2Н)), 6.65 (094, 2- 0.9; 2.4 and 7.8 Гм, 1Н), 7.16 (ii, 2- 7.8 Hz, 18), 7.24 (aaY, 11.2; 1.8 and 8.1 Hz, 1), 7.58 (y, 251.2 Hz, 1H), 7.64 (4, 7: 9.3 Hz, 18), 7.67

Zo (31-2.1 Hu, 1H), 7.88 (40.42 2.1 and 9.0 Gy, 1H)), 8.04 (0.1- 3.6 Ho, 1NU, 8.26 (4, 34- (He) 1.8 Gy, 1H), 8.47 (bg, 1H, MH), 8.71 (Bg, IN, MNU; 19E NMR (282 MHz, acetone-dbu: 7 -167 .73; LC/MS: retention time: 72.55 minutes; purity: 85.4395; MS (mass/charge): 490.97 (MN). 7.3.A72 M4-(2-carboxybenzofuran-5-yl)- 5-fluoro- | Similar to the preparation of 142,M4-bis(Z-carboxyphenyl)-5-fluoro-2,4-

Mm2-(3-(5-methyl--1,2,4-oxadiazole-3-pyrimylindiamine, M4-(2-carboxybenzofuran-» 5-17)-5-fluoro-M2-13-(5-methia-1 ,2,4- "yl)umethyleneoxyphenyl)-2,4-oxadiazol-3-yl)methyleneoxyphenyl-2,4-pyrimidinediamine is obtained as a result of pyrimidinediamine (2945134) reaction of 5-fluoro-M4-(2--methoxycarboni lbenzofuran-5 -1L)-M2-I3-(5-Methyl-1,2,4-iso-oxadiazol-3-yl)methyleneoxypheni-2,4-pyrimidinediamine (20 mg, 0.04 mmol) and. with Mahon (10 mg, 0.25 mmol). IN NMR (acetone-db):6 2.63 (5, ЗН), 5.04 (5, 2Н), 6.64 (y, ch te B Сy, 18, 7.17 0.72 81 Hz, 1Н ), 7.26 (d, 22: 7.8 Gy, 1H), 7.56 (5, NN), 7.62 (y, 1st and - 9.3 Gy, 11), 7.67 ( 6 18, 7.86 (ai, 1 1.8 and 9.0 Gy, 1H), 8.04 (0.7--3.3 Hz, IN), 8.26 (da, 1), 8.48 lg , IN, MN), 8.71 (g, IN, MA); РХ/MS: retention time: 18.00 min.; purity: 75.1395; MC (m/z): 476.70 (MN). 7.3.473 Mm4-(2-aminocarbonylbenzofuran-5-yl)»- Mixture of 5-fluoro-M4-(2-methoxycarbonylbenzofuran-5-yl)-M2-|3-(5-methyp-1,2,4- 5 -fluoro-M2-13-(5-methyl--1,2,4-oxadiazol-3-oxadiazol-3-yl)methyleneoxyphenyl|.-2,4-pyrimidinediamine (20 mg, 0.04 mmol) and (oh) Z-yl)umethyleneoxyphenyl|-2,4- concentrated MNAOH (5 ml) was stirred in methanol (5 ml) at room temperature pyrimidinediamine (2945135) overnight. The solvent is evaporated, obtaining M4(2-co (aminocarbonyl)benzofuran-5-1l|-5-fluoro-M2-Y3-(5-methyl--1,2,4-oxadiazol-3-ylumethyleneoxyphenyl|-2,4- pyrimidinediamine. IN NMR (acetone-4y6):0 2.61 (5, ZN), shk 5.04 (5, 2NI), 6.654 (444.12:0.9, 2.4 tav Hz, 18), 7.160 128.1 Go, 1), 7.27 (da, 15 0.9, 1.8 and 8.4 Hz, 1), 7.44 (a, 2:0.6 Gy, IN), 7.55 (39, 120.6 and 8.1 Hz, 1H), 7.64 (5 24.1), 7.79ad, 1- 2.4 and 9.0 Gy, IN), 8.03 (y, 3 - 3.6 Gy, IN), 8.24 (9.5-2.4 s Hz, 1H), 8.48 (g, 1H, MH), 8.68 (g, 1H, MH); 19 E NMR (282M Hz, acetone-4b):0-42) ko 60 b5

167.80; LC/MS: retention time: 7.43 min; purity: 10095; MS (m/z): 475.62 (MN). 7.3.474 5-fluoro-M4-(3-hydroxyphenyl)-42-14-(2- Similar to the preparation of M2,IM4-bis(4-(2-methoxyimino(amino)ethyleneoxy)phenyl)methoxyimino(amino)ethyleneoxy)phenyl )- 5-fluoro-2,4-pyrimidinedimine, 5-fluoro-M4-(3-hydroxyphenyl)-M2-14-(2-2.4-pyrimidinediamia (KU45167) methoxyimino(amino)ethyleneoxy)phenyl-2,4-pyrimidinedismin (40 mg, 7005) is obtained as a result of the reaction of 2-(4-cyanomethyleneoxyphenyl)-5-fluoro-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (50 mg, 0.14 mmol), methoxyamine hydrochloride (0, 71 mmol) and tristylamine (0.7 ml, 1.4 mmol). IN NMR (SOSIS):6 3.82 (5, ZN), 4.50 (5, 2H), 4.87 (Bi, NI, MN), 5.60 (ai, 1- 0.9, 2, 4 ha 8.1

Gy, IN), 6.79-6.84 (t, 2NI), 6.86 (y, 3- 8.7 Gy, 2NI), 7.00 (5, 1), 7.14 SE, 3- 8.1 Sy,

IN), 7.34 (a, 1-90 Hz, 2H), 7.47 (05-21 Hn, IN), 7.87 (a, 1- 3.3 Hz, TN); 192 YAME (282M Gy, SOSIZU6-167.67; RH/MS: retention time: 13.69 min, purity: 70 92.5152; MS (m/3): 399501 (MN). 7.3.475 M2-(3 ,4--styrenedioxyphenyl)-5-fluoro-M4A- / In a similar way to obtain M2,M4-bisi4-(2-- 14-methoxyimino(amino)styreneoxyphenyl|- | methoxyimiamino)ethyleneoxyphenyl)|-5-fluoro-2 . -

M2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine, methoxyamine hydrochloride and triethylamine. IN NMR (acetone-db6): 5 3.70 (5, ЗН), 4.21-4.28 (t, 4Н), 4.48 (5, 2Н), 5.46 (g, 2Н)), 6.71 (0, 1: 8.7 Gy, IN), 6.99 (4, 1: 90 Gu, 2H), 7.06 (va, 2.4 and 8.7 Hn, 1), 7.42 (0.12 2.4 gy, PN), 7.72 (a, 2: 9.3 gy, 2A), 7.93 (a, 3- 3.3 gy, 1H), 8.22 (ih, IN, MN), 8.40 (g, IN, MN); 192 NMR (282M Gy, acetone-46):0- 169.05; PH/MS: retention time: 16.49 min.; purity: 96.4795; MS (m/z): 440.96 (MN). 73476 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Mixture M24(3-ethoxy/or methoxycarbonylmethyleneoxyphenyl)-M4-(3,4" (340h- ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (19.8 g, 45 mmol), methylamino)carbonylmethyleneoxyphenyl|- | of methylamine hydrochloride (30.63 g, 450 mmol) and diisopropylethylamine (78.07 ml, 2,4-pyrimidinediamine (K926495) 450 mmol) in MeOH (450 ml) are stirred in a flask with ice under pressure at a temperature of 100 oC for 8 hours (3 subsequent thin-layer chromatography). The reaction mixture is cooled to room temperature, dissolved in H2O (6 liters), the resulting solid is filtered off, washed with H2O and dried, obtaining 18 g of M4-(3,4-ethylenedioxyphenia)-5-fluoro-M2-/3-(M-methinaminocarbonylmethylethoxyphenyl )|-2,4-pyrimidinediamine, In other words, M4- (3,A-ethylenedioxyphenyl)-5-fluoro-M2-|3-(M-methylamino)carbonylmethyleneoxyphenyl|- se 2,4-pyrimidinediamine is obtained as a result of the reaction equimolar amounts of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-aminopyridine and 34(M--o methylamine)carbonylmethyleneoxyaniline in MEOH in a flask under pressure at a temperature of 10 o C for 24 hours and or in EEON with microwave heating at a temperature of 175 o C for 10-20 min. followed by treatment with an aqueous solution. IN NMR'(CO3O):CI 7.90 (5, 10), 7.89 (b5, 1), 7.38 (b, 1Н, 7- 2,А Сy), 7.28 (8, 1Н, 122.4 Gy), 7.17-7.09 (tt, 2), 6.79 (9, 1H, 1-9 Hz), 6.57 (t, 18), "se 4.38 (85, 21), 4.24 (in, 4H), 2.81 (5, ЗН); PH/MS: retention time: 18.20 min.; purity: 9895; MS (m/z): 426 (MN.Yu). b 7.3.477 Ма1,4 benzoxazin-b-yl)-5-fluoro-М2-(3- methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimylindiamine, MA(1,4-benzoxazine-methylaminocarbonylmethyleneoxyphenyl|- | 6-yl)-5-fluoro-M2-(3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4- h - 2.4-pyrimidinediamine (K921219) pyrimidinediamine is obtained as a result of the reaction of MA-(1,4-benzoxazin-b-yl)-M2-(3-ethoxycarbonylmethyleneoxyphenia)-5-fluoro-pyrimidinediamine and semetnamine hydrochloride. IN NMR (SOZORI C 7, 8 (y, 18), 7.4 (t, 1H), 7.05 (t, 2 7.0 (5, 1), 6.8 (4, IN), 6.66 (4, IN), 6, 56 (64, 1), 4.35 (z, 2H), 4.18 (t, 2NU, so 3.25 (t, 2NI), 2.8 (5, ZN); РХ/MS: duration of retention: 18.0 min., purity: 9795;

MS (mi): 425 (MIU). 7.3.478 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-(M- (44(M-2-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, MA(3,4- hydroxyethylamino) carbonylmethyleneoxy | ethylenedioxyphenyl)-5-fluoro-M2-14-(0х-2- « phenyl|-2,4-pyrimidinediamine (5909239) tihydroxyethynamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine is obtained as a result of the reaction M4-(3,4- ethylenedioxyphenyl)-5-fluoro-Yim2-(4-ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and 2-hydroxyethylamine. - s IN NMR (020 r g 8.02 (0, 1H, 12 4 Ho), 7.40 ( t, 2H), 7.28 (t, 1), 7.05 (t, 5H), 4.83 (8, 2H), 4.5 (t. 2 HO), 4.23 (t, 7) , 4.93 (t, 2H), 3.87 (t, 2H); LC/MS: n » retention time: 17.17 min; purity: 9495; MS (m/z): 456 (MN. .A79 М4-(3,4-ethylenedioxyphenyl)-3-fluoro-(4- In a method similar to obtaining х4-4(3,4-ethylenedioxyphenyl)-5-fluoro-im2-|34(М-(М methylamino )carbonylmethyleneoxyphene p|-2,4-pyrimidinediamine, MA(3,4-methylamino)carbonylmethyleneoxyphenyl|-|ethylenedioxyphenyl)-5-fluoro-(4-(M-methylamino)carbonylmethy lenoxyphenyl|-2,4- 2,4-pyrimidinediamine (K909240) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-

Go! ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4-(M-methylamino)carbonylmethyleneoxyaniline. 1H NMR (20:11 8.02 (0, 1H, 12:45 Gy, 7.40 (t, 28), 7.28 (t, 18), 7.05 (t, 5), 4.83 ( z, 28), 4.5 (t, 2H), 4.23 (t, 2H), 3.87 ko (5, ZN); LC/MS: retention time: 18.43 min.; purity: 9495; MS (m/z): 426 (MH). - MA-(1,4-benzoxazine-b-yne)-5-fluoro-2-(3-. | Similar to the preparation of M4-(3,4-ethylenedioxyphenium)- 5-fluoro-M2-(3-(M-(Ce) (42) ko 60 b5

(M-2-methylamino)carbonylmegyloxyphenyl|-2,4-pyrimidinediamine, M4(1,4-benzoxazine-hydroxypropylamino)carbonylmethylene | 6-yl)-5-fluoro-m2-13-014-2-hydroxypropylamino)carbonylmethyleneoxyphenyl-2,4-siphenyl|-2,4-pyrimidinediamine (KU09251) | pyrimidinediamine is obtained as a result of the reaction of M4-1,4-benzoxazi n-b-yl)-M2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine and 2-hydropropylamine. IN NMR (0М50-46): H1 7.99 (d, IN, 1254 Hz), 7.25 (t, 72Н), 7.04 (t, 1НУ, 6.82 (t, 2Н), 6.58 (t, IN), 6.45 (t, 1) 4.36 (5, 2H), 4.02 (t, 2H), 3.75 (t, 1H)), 3.31 (t, 28) , 3.00 (t, 2H), 1.00 (t, ZN); PH/MS: retention time: 17.33 min.; purity: 9795; MS (m/z): 469 (MNK), 7.3.481 M4-(1,4-benzoxazin-b-1l)-5-fluoro-1M2-13- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-13-40M- (Msh-3-methylamino)carbonylmethyleneoxyphene l1-2,4-nyrimidineliamine, IM4(1,4-benzoxazine-hydroxypronylamino)carbonylmethylene | β-yl)-2-fluoro-12-13-(0M4-3-hydroxypropylamino)carbonylmethyleneoxyphenyl|-2,4-siphenyl)-2,4-pyrimidinediamine (K909252) | pyrimidinediamine is obtained as a result of the reaction of M4-(1,4-benzoxazin-b-1l)-M2-13-70 enzicarbonylmethyleneoxyphenyl|-5-fluoro-2,4-pyrimidinediamine and 3-hydroxypropylamine. IN NMR (PMO-46): SI 7.99 (b, IN, 4-4 Hyd), 7.39 (t, 2H), 7.04 (t, 18), 6.87 (t, 2H), 5.55 (t, 19), 6.41 (t, 1H), 4.29 (z, 2NU, 4.02 (t, 2H), 3.35 (t, 2H, 3.31 (t 2H) . -(1,4-benzoxazin-6-yl)-Mm2-(3-04- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-13-0h- isopropylamino)carbonylmethyleneoxyphene | methylamino)carbonylmethyleneoxyphenyl| -2,4-pyrimidinediamine, IM4A-(1,4-yl)-3-fluoro-2,4-pyrimidinediamine benzoxazine-6-1l)-5-fluoro-M2-I3-(M-isopropylamino)carboniamethyleneoxyphenyl)-2 ,4- (5909254) pyrimidinediamine is obtained as a result of the reaction of MaA-(1,4-benzoxazin-6-yl)|-M2-(3- ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-nyrimidinediamine and isopropylamine. 1

NMR (РМ50-46):0 7.79 (0, IN, U- 4 Hz, 7.25 (t, 1Н), 7.14 (t, IN), 7.02 (n 18), 6.85 (t, ZNU, 6.63 (t, 1), 4.39 (5, 2), 4.12 (pz, 2), 4.05 (t, 1H), 3.38 (t, 7H), 1.20 (t, 6H); LC/MS: retention time: 20.83 min; purity: 967; MS (m/z): 453 (Mn. 7.3.483 5-fgor-M4-(4-isopropoxyphenyl) -M2-(2- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-13-(M-(M-pyrrolidino)carbonylbenzofuran-5-methylamino)carbonylmethyleneoxyphenyl1-2,4-pyrimidinediamine, 5- fluoro-M4-(4-yl-2,4-pyrimidinediamine (K926703) isopropoxyphenyl)-M2-(2-(M-trolidino)carbonylbenzofuran-5-1l|-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-fluoro- M2-(2-Methoxycarbonylbenzofuran-5-yl)-M4-(4-isopropoxyphenyl)-2,5-pyrimidivdiamine and pyrrolidine. IN NMR (SOSIS: 7 7.83 (z, 1H), 7.794, 1H, 2: 5 ... .7 Hz), 4.52 (20, 1H, 1-60 71), 3.92 (0, 2H, 3- 6.9 Hn), 3.67 (1, 2H, 1- 6.9 p) , 2.05-1.90 (t, 4H), 1.32 (4, s

H,1- 6.6 Hz; 1I9E NMR (SOSIZ):-24000; PH/MS: retention time: 23.49 min; purity; 9795; MS (m/z): 476 (MN). o 7.3.484 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-ych2-(3-05-

I4-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3,4- methylamino)carbonylmethyleneoxyphenyl- | ethylenedioxyphenyl)-5-fluoro-M2-(4-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-2.4-pyrimidinediamine (KO26708) pyrimidinediamine is obtained as a result of the reaction of M4-(3,4-styrenedioxyphenyl)-5-(Che)fluorine -m2-(4-metho oxycarboni lmethyleneoxyphenyl)-2 zA-typyrimidinediamine and methylamine hydrochloride. IN NMR (0ЮМ50-46):0) 10.10 (B5, IN), 9.88 05, 1НУ, 8.15 F (Б1Н ,2-4.5 Go), 8.05 GbB, 1H), 7.40 (4, 2H,3- 8.7 Hz), 7.23 (4, 18, Re 2 Gy), 7, (40 , IN, 1-24 and 8.7 Hz), 6.89 (4, 2H, 1- 8.7 Hz), 6.81 (y, 1H, 32: 8.7 Hz), 4.42 (5 , 2H), 4.23 (in, 4H), 2.64 (4, ЗН, 12 4.5 Hn); PH/MS: retention time: 17.60 min; Che purity: 9695; MS (m/z): 426 (MN). 7-3,485 MA-(4-tert-butylphenyl)-5-fluoro-M2-(2- Analogous to the preparation of M4-(ethylenedioxyphenyl)-5-fluoro-M2-(3-(M-se (M-methylamino)carbonylbenzofuran- 5-methylamino)carbonylmethyleneoxyphenyl |-2,4-pyrimidinediamine, M4-(4-tert-3in|-2,4-pyrimidinediamine (KO26404) butylphenyl)-5-fluoro-M2-12-(M-methylamino)carbonylbenzofuran- 5-yl1-2,4-(ge)pyrimidinediamine is obtained as a result of the reaction Ma-(4-tert-butylphenyl)-3-fluoro»

M242-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and methylamine hydrochloride. IN NMR (SOZOYUIS 8.04 (a, 1H, I: 2.4 Hn), 7.88 (0, 1H, 4.2 Hn, 7.58-7.30 (t, 7H). 2.94 ( 5, ZN), 1.33 (z, 9H); LC/MS: retention time: 22.56 min; purity: 9495; MS (m/z): 434 (MNK). " 7.3.486 M4-(4 -tert-butylphenyl)-5-fluoro-ych2-14- Similar to the preparation of I44-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-(M-(M. methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimipineliamine , MA (4-tert-shch methylamino)carbonylmethyleneoxyphenyl-|butylphenyl)-5-fluoro-M2-14-47M-methylamino)carbonylmethyleneoxyphenyl)-2,4-s 2,4-pyrimidinediamine (8926712) pyrimidinediamine is obtained as a result of reaction M4 -(4-(tert-butyl)phenium |-5-fluoro- and M2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and i - methylamine hydrochloride. 1 H NMR (SOYUZOUHK I 7.92 (4, 1H, 72 5.4 Hz), 7.538, ZN, 1-8.7 Hz), 7.40 (0, 2H, 1-2 8.7 Hz), 7.34 (d, 2H, 22 8.7 Hz), 7.03 (9, 2H, 12 8.7 Hz), 4.52 (5, 2H), 2.82 (5, ЗН), 1.35 (5, УН); 19E NMR (SOZOI): -46174 ; LC/MS: retention time: 23.34 min; purity: 9499, MS (m/z); 424 (MH), 7.3.487 Ma-(3-tert-buty iphenyl)-5-fluoro-M2-(3- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-I3-(M-(ee) (M-2-methylamino)carbonylmethyleneoxyphenyl-2,4 -pyrimidinediamine, M4-(3-tert-- hydroxyethylamino)carbonylmethyleneoxy | butylphenyl)-5-fluoro-M2-H/3-0m-2-hydroxystylamino)carbonylmethyleneoxyphenyl|- co phenyl|-2,4-pyrimidinediamine (K940295) 2.a-pyrimidinediamine is obtained as a result of the reaction M4-(3-tert -butylphenyl)-5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and 2-- - hydroxyethylamine. PH/MS: retention time: 21.34 min; purity: 9795; MS (m/z): 453 (Mk); 454 (MN); 1 N YAM? (SOSIZ)-: 1 10.34 (IN, 5), 7.76 (1H, ti), 7.52 and pH, tu, 74-71 (5Н, t), 6.98 (IN, t), 6.7 (1), tu, 4.36 (28, 5), 3.77 (2H, 1 5 Go), (Se) 42) ko 60 b5 and 3.51 (2H, t), 1.27 (9H, 5). 7.3.485 M2,M4-bisi4-4(M. Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-I3-(M-pyrrolidino)carbonylmethyleneoxyphenyl)!- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 142.M4-bist4-(M-5-ethoxycarbonyl-2.4-pyrimidivdiamine pyrrolidino)carbonylmethyleneoxyphenyl|-5-ethoxycarbonyl--2,4--pyrimidinediamine (8926562) is obtained as a result of the reaction M2.M4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-2,4-pyrimidinediamine and pyrrolidine. TAN NMR (PM5O-46X:0 10.17 (5, IN), 8.73 (B5, IN), 7.50 (6d, 2Н, 19.0 Hz), 7.43 (d, 2Н, I: 2.4 and 6.9 Hz), 6.91 (t,

AN), 4.64 (5, 2H), 4.62 (v, 2H), 4.34 (d, 2H, 2-7.2 Gy), 3.53 (t, 8H), 1.95 (t, 4H), 1.86 (t, 4H), 1.38 (6, ЗН, /- 6.9 Gy); LC/MS: retention time: 22.54 min; purity: 10095; MS (m/z): 590 (MN.Yu). 7.3.489 М2,М4-bis(4-М- Analogous to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-И3-05-pyrrolidinocarbonylmethyleneoxyphenia)- methypamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M2, M4-bis 14-4(M-70 5-fluoro-2,4-pyrimidinediamine (KU26563) pyrrolidino)carbonylmethyleneoxyphenyl|-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M2,M4-bis(4-methoxycarbonylmethyleneoxyphenyl) -5-fluoro-2,4- pyrimidinedismine and pyrrolidine. 1H NMR (SOSIZ) C 7.90 (5, 1), 7.50 (64, 2H, 2 7.8 Gy). 7.41 (60, 2H, 2 7.2 Go), 6.93 (t, 4H3, 6.73 (5, 1), 6.64 (5, MH), 4.65 (5, 18), 4.65 (5, ANI), 3.54 (t, BN), 1.96 (tv, 48), 1.87 (tyu, 4H). 7.3.290 Ma-(3-tert-butylphenyl)-M2 -13-(014-41,3- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-4(M-dihydroxypropyl-2» methylamino)jarbonylmethyleneoxyphenyl|-2,4-pyrimidineliamine, MA (Z-tert-amino)carbonylmethyleneoxyphenyl|-5-butylphenyl)-Ch2-I1-3-11,3-dihydroxypropyl-2-amino)carbonylmethyleneoxyphenyl|-5-fluoro-2,4-pyrimidinediamine (K940296) fluoro-- 2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(3-tert-butylphenyl)-5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenyl|--2,4-pyrimidinediamine and 2-amino-1,3-propanediol. РХ/ MS: retention time: 70.26 min; purity: 97.67; MS (m/z): 484 (Mk); 485 (MNY); IN NMR (ОМ50-а6КО 9.75 (1Н, 5), 9, 57 (1H, 5), 8.25 (IN, t), 7.92 (IN, t), 7.62 (2H, t), 7.37 (ЗН, t), 7.23 (IN, t ), 6.66 (IN, t), 4.46 (OH, 5), 3.87 (1H, g), 3.55 (AN, pi), 1.36 (OH, 5). 7.3.491 M2-I3-(M-2,3- Similar to the preparation of M4-( 3,4-ethylenedioxyphenyl)-5-fluoro-M2-|34(M-dihydroxypropylamino)carbonylmethylene | methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M2 (3-(M-2,3-oxyphenyl|-5-fluoro-M4-(3-dihydroxypropylamino)carbonylmethyleneoxyphenyl)-5-fluoro-M4-(3-isopropylphenyl)- isopropylphenyl)-2,4-pyrimidinediamine 2,4-pyrimidinedismine is obtained as a result of the reaction of 5-fluoro-Mm4-4(3- (K940290) isopropylphenyl)-M2-(3--methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and З- of amino-1,2-propanediol. LC/MS: retention time: 20.04 min; purity: 9828; MS (m/z): 470 (MH and H NMR (YUM50-a6y 1 9.54 (1H, 5), 941 PN, 5), 8.22 (IN, p"), 7.95 (1H, po , 7.85 PN, 9, 1-10 Hn), 7.58 (1H, 5), 7.43-7.32 (ZN, t), 7.25 sem (non 7.75 GI), 7, 06 (1, y, ze 7.75 Nu, 6.64 (1H, 4, 42:10 Hz), 4.47 (2H, 5), 3.38 7 o y (YAN, t), 3.16 (IN, t), 2.96 (1H, n), 1.28 (6H, y, 16.9 Ha). 7.3.492 5-fhor-M4-(3-isopropylphenia)-Mm2-13-(0M - | Analogous to the preparation of Im4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-(M-methylamino)carbonylmethyleneoxyphenyl|methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidikidiamine, 5 fluoro-M4-(3- - ,4-pyrimidinediamine (8940288) isopropylphenyl)-M2-I3-(M -methylamino)carboniamethyleneoxy)phenyl|--2,4-pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M4-(3-isopropylphenyl)- (Che)

M2-3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and methylamine hydrochloride. LC/MS: retention time: 23.43 min; purity: 9905; Ge

MS (mizu: 409 (M), 411 (MNK); 1 H NMR (OM50-a46u7I 9.90 (1H, 5), 9.74 (1H, c), 8.28 PIN, a, 1-48 Hyd), 8.06 (1, t), 7.78 (IN, d, 22: 7.2 Gy), 7.58 (1H, 8), 7.4-7.3 (ZN, tu, 7.24 ( IN, 1.2: 8.4 Gy), 7.00 (IN, 8, 1- 7.25 Hn), 6.79 (IN, d, 12: 7.25 Hz), 2.44 (2Н, ch 5), 2.93 (IN, zer, 1- 6.9 Gy), 2.745 (ZN, d, 1- 4.8 ГЦ), 1.27 (6Н, 4, 1- 6.9 Gy). 7.3.493 5-fluoro-M4-4(3-hydroxyphenyl)-M2-12-(M- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(M- se dimethylamino) carbonylenzofuran-5-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinethiamine, 5-fluoro-M4-(3-ylI-2,4-pyrimidandiamine (K926718) hydroxyphenyl)-M2-(2-(M-dimethylamino)carbonylbenzofuran-5- yl)-2,4-s pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M4-(3-hydroxyphenia)-M2-(2-methoxycarbonylboenzofuran-5-yl)-2,4-pyrimidinediamine and dimethylamine.

NMR (SOS 8.06 (4, IN, 72 2.1 Go), 7.91 (4, IN, 15 3.6 Hz), 7.57 (0, IN, 12 24

Hy), 7.374, 1H, 3-90 Hy), 7.28 (5, 1H), 7.19 (b TAN, 3-- 7.8), 7.06 (5, 1H), 6.82- 6.76 (t, 2H), 6.71 (44, 1H, 2- 2.4 and 7.8 Hz), 3.31 (5, ZNI), 3.09 (5, ZNU; 192 NMR (SOSIZ ):-47292; LC/MS: retention time: 17.29 min; purity: 9295; MS (m/z): « 408 (MN. 7.3.494 Ma4-(3-chloro-4-hydroxy-5-methylphenyl )-5- | Analogously to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-13-(М- - with fluoro-М2-13-(М- mechthylamino)carbonylmethyleneoxyphenyl|. 2,4-nyrimidinediamine, M4-(3-chloro-4-piperazino)carbonylmethyleneoxyphenyl|- ) hydroxy-5-methylphenyl)-5-Fluoro-M2-|3-(M-piperazino)jarcarbonylmethyleneoxyphenyl|-

GU 2,4-pyrimidinediamine (K945149) 2,4-pyrimidinediamine (520 mg, 66925) is obtained as a result of the reaction of M4-(3-chloro-4- and »tihydroxy-3-methylphenyl)-5-fluoro-M2-(3 -methoxycarbonylmethyleneoxyphenyl)-7,4-pyrimidinediamine (700 mg, 1.6 mmol) and piperazine (4 g, 46 mmol). IN YAME (SOZOYUKO 2.22 (5, ZN), 2.75 (1.12 5.4 Hz, 48), 3.40 (5, 1: 4.8 Hz, 2H), 3.54 (12 5 ,1

Hz, 2), 4.62 (5, 2H), 6.57 (444, Re 1.5,2.7 and 7.5 Hz, 1H), 7.09 (4, 251.5 and 81 Hz, 1 , 7.14( 157.8 Hz, 15), 7.28 (3-21 Hz, IN), 7.31 (44, 7 x 0.9 and 2.7 Hz, IN), about 7.504, 1 - 2.7 Go, 1H)U, 7.88 (9, 1-3.9 Gy, 1H); I9E NMR (282 MHz, SPZOV) - 168.63; PH/MS: retention time: 14.99 min; 93.8895; MS (m/z); 486.96. - (M-methylamino)carbonylbenzofuran-5-methylamino)carbonylmethyleneoxyphenyl| 2,4-pyrimidinediamine, M4 (4-tert--yl|-2.4-pyrimidinediamine (5.926713) butylphenyl)-5-fluoro-M2-(2-(M-methylaminocarbonylbenzofuran-5-yl|-2,4- ( Se) 42) with 60 b5 pyrimidinediamine, the result of the reaction 44-(4-tert-butylphenyl)-5-fluoro-

M2-2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and methylamine hydrochloride. IN NMR (COSOI): 7 8.05 (4, 1H, )- 2.4 Gy), 7.88 (a, 18, 1-42 Hz, 7.57 (98, 2H, 2- 8.7 tsu . 47682; LC/MS: retention time: 23.02 min; purity: 9092; MS (m/13: 434 (МН. 7.3.496 M4-(3,5-dimethoxyphenyl)-5-fluoro-1х2-13- Similarly preparation of 1х4-(styrenedioxyphenyl)-5-fluoro-m2-1|340- (M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4-(3,5- methylamino)carbonylmethyleneoxyphenyl! | dimethoxyphenyl)-5-fluoro-M2 -Y34(M-methylamino)carbonylmethyleneoxyphenyl|-2,4- -2,4-pyrimidinediamine (926796) pyrimidinediamine is obtained as a result of the reaction M443,5-dimethoxyphenyl)-M2-(3-stoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4 -pyridinediamine and methylamine hydrochloride, 1H NMR (SPZOYUKI 7.929, 1H, 242 Hz), 7.42 (IN, 1-1.8 Hz, 7.12 (t, 2H), 6.91 (a, 18, 1-24 n), 6.59 (t, 18), 6.22 (I, 18, 1: 1.8 Go), 4.35 (8, 2), 3.69 (5, 5H), 2.81 ( z, ZN); RH/MS: retention time: 18.35 min; purity: 9395; MS (m/z): 428 (MN). 7.3.497 5-E toxycarbonyl-M4-(3,4- Analogous to the preparation of M4-(ethylenedioxyphenyl)-5-fluoro-m2-|34(M- ethylenedioxyphenyl)-2-13-(H- methylamino)carbonylmethyleneoxyphenyl--2,4-pyrimidinediamine, 5 -stoxycarbonyl-methylimino)carbonylmethyleneoxyphenyl) | M4-(3,4-ethylenedioxyphenyl)-M2-|3-(M-methylamino)jarcarbonylmethyleneoxyphenyl|-2,4- -2,4-pyrimidinediamine (K926800) pyrimidinediamine is obtained as a result of the reaction of 5-ethoxycarbonyl-M2-(3- ethoxycarbonylmethyleneoxyphenyl)-Ma4-(3,4-ethylenedioxyphenyl)-2,4-pyridinediamine and methylamine hydrochloride. NMR (YUM5O-yb): 7 19.05 (5, 1), 9.34 (5, 1H), 8.69 (5, 1H), 7.95 (8, IN, 1-2 4.8 Hz), 7.34 (44, 1H, in: 1.2 and 7.8 Gy), 7.25 (B5, 2H), 7.13 (, 1H, 3-81 Go), 7.00 (Ba , 1H, 12 9Hz), 6.81 (0, 1H, 1e 8.7 Go), 6.59 (04, 1H, 1- 1.5 and 8.4 Gy), 4.32 (5, 7NU, 4.30 (4, 2H, 72: 7.2 Hz), 4.21 (5, 4H)), 2.63 and 2.62 (2v, ZA), 1.31 (6 ZN, le 7.2 Hzu; LC/MS: retention time: 24.12 min; purity: 9195; MS (m/z): 481 (MN). 7.3.498 M443,5-dimethoxyphenyl)-5- Similar to the preparation of M4-(ethylene lyoxyphenyl)- 5-fluoro-k2-(3-40M - stooxycarbonyl-iM2-13-0M. methylaminocarbonylmethyleneoxyphenyl)|--2,4-pyrimidinediamine, M443,5- methylamino)carbonylmethyleneoxyphenyl! | dimethoxyphenyl)-2-ethoxycarbonyl-M2-13-(M- -4-pyrimidinediamine (K926801) methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction MA-(3,5-dimethoxyphenyl-5-ethoxycarbonyl-M2- (3-ethoxycarbonylmethyleneoxyphenyl)-2,4-pyridinediamine and methylaminehydrochloryl.

IN NMR (0M5O0-46): 2 10.20 (5, 18), 9.96 (5, 1H), 8.73 (5, 1), 7.90 (B5, 1NU, 7.36 (4, 1H.31- 8.7 Gu, 728 05, AN), 712 0 IN, 7- 7.5 Gy), 6.84 (5, 2H), 6.59 (44, IN, 1- 1.8 s and 85.1 Hz), 6.25 (0 1Н, 1-24 их), 4.31 (t, 48), 3.67 (5, 6Н), 2.63 and 2.62 (2е, ЗН), 31 with ZN. 1-5 7.2 Gy); LC/MS: retention time: 25.50 min; purity: 9695; MS He) 0707Й72-- сх ВЕ (МНt; 7.3.499 Ma44-tert-butylphenyl)-5-fluoro-M2-Y3- Analogously to the preparation of IM4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-Y340M- ( m. methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, Ma (4-tert-methylamino)carbonylmethyleneoxyphenyl|- | butylphenyl)-5-fluoro-42-|34(M-methylamino)carbonylmethyleneoxyphenyl)--2,4-(Ce) 2,4-pyrimidinediamine (K926714y pyrimidinediamine is obtained as a result of the reaction M4-(4-tert-butylphenium)-5 -fluorine-

M2-43-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinedimine and b methylamine hydrochloride. IN NMR (SOZOUI:C 7.90 (d, 1, 2: 3.3 Hz), 7.61 (a, 2, 31-8.7 Hz), 7.40-7.33 (t, ZN) , 7.14-7.11 (t, 2NI), 6.62-6.57 (t, 1NU, 4.36 (5, 2H), 2.79 (8, Z), 1.31 (5, 9NU; 192 NMR (SOZOB): -47514; LC/MS: retention time: 23.70 min; purity: 9395; MS (m/z): 424 (MN). 7.3.500 M4-(3-hydroxyphenyl) -5-trifluoromethyl- Analogous to the preparation of I44-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-H34(M- with

M2-I340M- methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, MA (3-

Zo methylamino)carbonylmethyleneoxyphenyl) | hydroxyphenyl)-5-trifluoromethyl-M2-(3-(M-methylamino)carbonylmethyleneoxyphenyl|- co -2,4-pyrimidivdismin (926742) 2,a4-pyrimidinediamine is obtained as a result of the reaction IM4-4(3-hydroxyphenyl)-5- trifluoromethyl-M2-(3-methoxycarbovylmethyleneoxyphenyl)-2,4-pyrimidinediamine and methylamine hydrochloride RA/MS: retention time: 19.11 min, purity: 9995;

MS (mi): 434 (MN). 7.3.501 5-fluoro-M4-CI1 H)-indol-b-yl|-M2-13-0M- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-Ffluoro-Mm2-|3-0M- methylamino)carbonylmethyleneoxyphenyl| | methylamino)carbonylmethyleneoxyphenyl|--2,4-pyrimidinediamine, 5 fluoro-MA-KIN)- -2,4-tarimidinedismin "(K926745), indole-b-yl|-M2-13-4h-methylamino)carbonylmethyleneoxyphenyl-2, 4-pyrimidinediamine 8c is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-KiH)-indol-b-yl|-4-pyrimidinamine and 3-(M-methylamino)carbonylmethyleneoxyaniline. RH/MS: h duration of retention: 17.41 min; purity: 9305; MS (m/z): 407 (MN B). more » 7.3.502 44-(3,5-dimethyl-4-methoxyphenyl)-5- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-13-0M- fluoro-M2-|3- (M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3,5-dimethyl-4-piperazino)carbonylmethyleneoxyphenyl|- | methoxyphenyl)-5-fluoro-M2-13-(M-piperazino)carbonylmethyleneoxyphenyl-2,4-2,4-pyrimidindiamine (5945156) pyrimidinediamine is obtained as a result of the reaction M4-(3,5-dimethyl-4-methoxyphenyl)-5 -fluoro-M2-(3-methoxycarbonylmethylene oxyphenyl)-2,4-pyrimidinediamine and so piperazine. NMR (CO3ZOYUU 6 2.23 (5, 6H), 3.24 (t, 4), 3.71 (8, ZN), 3.72-3.81 (pu, ANU, 4.75 (v, 2H), 6.81 (a 37-32 and 8.1 g, 18), 7.10-7.13 (t, 2H), 7.24 (d, 15 8.7 ko Hz, 1 H), 7.29 (5, 2NI), 7.98 (y, 31--4.8 Go, NU, 19 E NMR (282M Hz, SOZOI):6- 163.88; LC/MS: retention time: 15, 94 min; purity; 10095; MS (m/z: 481.12 -kyi (MN. 7.3.503 4-(3-tert-butylphenyl)-5-phor-HM2-12- Analogously to the preparation of M4-(3,4 -ethylenedioxyphenyl)-5-fluoro-M2-13-0х4- (se) (Mi-methylamino)carbonylbenzofur-z-yl|- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, MA (3-tert- (42) ko 60 b5

2,4-pyrimidinediamine (8940291) butylphenyl)-5-fluoro-M2-(2-(M-methylamino)carbonylbenzofur-5-yl-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(3-tert-butnylphenyl)- 5-fluoro-

M2-(2-methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine and methylamine hydrochloride. LC/MS: retention time: 23.05 min; purity: 10095;

MS (m/z)y: 434 (MEN; 1 H NMR (OM5O0-46):2 9.6 (IN, 5), 9.57 (1Н, 5), 8.75 (IN, t), s 8.25 (IN, 5), 8.15 (IN, 5), 7.93 (IN, f, Re 8.5 Hz), 7.47 (ZN, p), 7.44 (1 H, 5 ), 736 IN, 8 21-8.5 Gy), 7.25 (IN, y, 1- 8.5 Gy), 2.89 (ZN, d, 3- 4.5 Gy), 1.33 ( 9H, 5). 7.3.504 МА4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2- 1 Similar to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-13-(М-

1-o-methylamino)carbonylmethyleneoxyphenyl)|-2,4-pyrmidinediamine, 1444(3,4-tihydroxyethylamino)carbovylmethyleneoxy | ethylenedioxyphenyl)-5-fluoro-M2-|3-(2-phenyl-2,4-thyrimidinediamine (2926505) hydroxystylamino)carbonylmethyleneoxyphenyl|- 2,4-pyrimidinediamine is obtained as a result of the reaction M4-(3,4-ethylenedioxyphenyl)-5 -fluoro-M2-(3-methoxycarbonylmethylevoxy)phenyl)-2,4-pyrimidinediamine and 2-hydroxyethylamine.

IN NMR (SOZOVuKO 7.87 (0, 1H, 2 3.6 Gy), 7.57 0, 1H, 151.8 Hz, 7.24 (0, IN, Te 2.4 Hz), 7.13 ( t, 2H), 7.08 (40, 18, 329.1 and 8.1 Gy), 6.77 (vv, IN), 4.38 (5.2NU 4.22 (5, ZN), 3, 63 (ii, 211), 3.40 y, 2H, 15 6 Gy), LC/MS: retention time: 16.72 min; purity: 9895; MS (m/z): 456 (MNK). 7.3.505 5-fluoro-М4-(3-hydroxyphenyl)-М2-(3-(М- |-2,4-pyrimidinediamine, 5 fluoro-M44(3-dihydroxypropylamino)carbonylmethylene|hydroxyphenyl)-M2-I3-(M-2,3-digylroxypropylamino)carbonylmethyleneoxyphenyl|-oxyphenyl|-2,4-pyrimidinediamine 2,4- pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M4-(3-hydroxyphenyl)-(8926746) M2-3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and 3-amino-1,2-propanediol, LC/MS: retention time: 12.84 min; purity: 9695; MS (m/z): 444 (MN. 7.3.506 5-fluoro-M2-(2-(2-hydroxy-1,1-) Analogously to the preparation of M4-(3,4- ethylenedioxyphenyl)-5-fluoro-M2-E3-(M-dimethylethyl mino)carbonylbsnzofuran- | methylamino)carbonylmethyleneoxyphenia|-2,4-pyrimidinediamine, 5 fluoro-M2-(2-(2-5-yl|-M4-(3-hydroxyphenyl)--2,4-hydroxy-1, I-dimethylethylamino)carsonylbenzofuran- 5-yl|-M4-(3-hydroxyphenyl)-pyrimidinediamine (926715) 2,4-pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M4-(3-hydroxyphenyl).

M2-(2-methoxycarbonylbenzofuran-5-1l)-72,4-pyrimidinediamine and 2-amino-2-methylpropanol. 1H NMR (0M50-y6)::7 9.41 (8, 1H), 9.28 (5, 150), 9.22 (5, IN), 8.18 (1, 1H, 72 2.4, Gy) , 8.09 (4, 18.45: 3.6 Hz), 7.56 (84, 1H, 12 24 and 8.7 Gy), 7.47 and,

IN, 1-87 Hz), 7.32 (5, EN), 7.26-7.21 (t, 1H), 7.13-7.07 (p), 2H), 6.535, 1H, 1 8 ,7

Hn), 5.05 1, 1H, 32 5.7 Hz), 3.46 (0, 2H, 32: 5.7 Hn), 1.32 (5, 6H); RH/MS: duration of sem retention: 17.93 min; purity: 970; MS (m/z): 452 (MNU. 7.3.507 5-fluoro-Ma-4(4-isopropoxyphenyl)-M2-I3- | Similar to the preparation of M4-(3,4ethylenedioxyphenyl)-5-fluoro-M2-13- 0M- o (M. methylamino)carbonylmethyleneoxyphenyl|-2,4-trimidinediamic, 5 fluoro-M4-(4. methylamino)carbonylmethyleneoxyphenyl | isopropoxyphenyl)- M2-|3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4- - 4-pyrimidinediamine (K926730) pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenyl)-M4-(4-isopropoxyphenyl)-2,4-pyrimidineliamine (Che) and methylamine hydrochloride. IN NMR (SOSIS): O0 7.930, 1H,1- 3.0 Hz), 7.47 (y, 2H,1-93 Gy), 7.421, 1: 8 Hz), 7.17 (5 IN, Re B .I Gi), 7.10 (B, NN), 7.00 (44,

IN, le 1.8 and 9.3 Hz), 6.89 (d, 2H, 12 9.3 Hyd), 6.80 (9, NN, 251.8 Hn), 6.58 (05, EN) , (2) 6.504, 1H, and 1.5 and 8.1 Go), 4.51 (29, IN, 5 5.7 Gy), 4.44 (5, 2H), 2.88 (4, ЗН , 15 4.5 Ha), 1.33 (y, 6H, ze: 5.7 Ha); 19E NMR (SOCI3):-47198; RH/MS: duration h-: retention: 19.66 min; purity: 9790; MS (m/z): 426 (MNK). 7.3.508 5-fluoro-m4-(3-hydroxyphenyl)-M2-14-(M- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-134(M- sem methylamino)carbonylmethyleneoxyphenyls | methylamino )methyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-M44(3- -2,4-pyrimidinediamine (K945170) tihydroxyphenyl).M2-(4-«M-methylamino)carbonylmethyleneoxyphenyl |-2,4- pyrimidinediamine are obtained as a result of the reaction of M2-4-cyanomethyleneoxyphenyl)-5-fluoro-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine and methylamine hydrochloride. IN

NMR (SRSIZ):6 2.91 (d,1- 5.1 Gy, ZA), 4.48 (5, 2), 6.61 (ad, 1-- 0.9, 2.7 and 8.1 Hz , 1H), 6.63 (g, IN), 6.76 (d, 1-3.0 Hz, 1H), 6.84-6.89 (iz, 4H), 7.18 (t, 7 8 ,1 Sy, KN), 7.44 (0, 1-87 Hz, 2H), 7.511: 2.1 Hz, 1H), 7.92 (db, IN); 19E NMR (282M Hu,

SRSIZ):6-167.70; LC/MS: retention time: 14.32 min; purity: 10095; MC « (m/z): 383.98 (MN). 7.3,509 5-fcor-M4-(3-isopropoxyphenyl)-M2-12- | Analogous to the preparation of M4-«(ethylenedioxyphenia)-5-fluoro-M2-(3-40M- - with (M-morpholino)carbonylbenzofuran-5-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-M4-(3 - yl)-2,4-pyrimidinediamine (K926489) isopropoxyphenyl)-M2-12-(M-morpholino)carbonylbenzofuran-5-yl|-2,4-p pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-mMa-(3- isopropoxyphenyl)- and » ЧМ2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinamine and morpholine. IN

NMR (SOSIZUO 8.01 (4, IN, I 1.2 Hz), 7.95 (v5, 1), 7.43-7.38 (t, 2H), 7.29 (5, 189), 7 ,25-7L1 (t, AN), 6.97 (v5, 1H), 6.73 (t, 180), 6.67 (rod, 1H), 4.48 (zer, 1H, 12 5.7 Gy), 3.87 (t, 4H), 3.79 (t, 4H), 1.30 (d, 6H, 1-5.7 Gy), РХ/MS: duration of retention: 22.12 ha, purity: 9852; MS (m/z): 492 (MNK). (ee) 7.3.510 5-fluoro-M4-(3-hydroxyphenyl)-m2-|3-014- Similar to the preparation of M4-(cetyldioxyphenyl)-5-fluoro-M2 -(3-0M- piperazino)carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-MA-(3-

КкЗз 2,4-pyrimidinediamine (926772) tihydroxyphenyl)-M2-13-(M-piperazino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M2-(3- ethoxycarbonylmethyleneoxyphenyl)-M4-(3- hydroxyphenyl)-2,4-pyrimilindiamime and piperazine. IN NMR (CO3OYU: 7.91 (0, 1H, 1-36 schu 72 (IN, 24 Hz, shk and 7.20-7.07 (t, 5H), 6.55 (t, 2H), 4.63 ( 5, 2H), 3.54 (I, 2H, 7-6 Hz), 3.40 (i, 2H, 7- 5.1 (Ce) 42) ko 60 b5

Gy), 2.75 g, 4H, 1-5.4 Gy); LC/MS: retention time: 12.98 min; purity: 9295;

MS (m/z)y: 439 (MNK). t3.m 5-fluoro-M443-hydroxyphenyl)-Mm2-I3-(M- Analogously to the preparation of M4-(ethylene lyoxyphenyl)-5-fluoro-M2-I34(M- 2-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-M4-4(3-hydroxyethylamino)carbonylmethyleneoxy|hydroxyphenyl)-M2-|3-(04-2-hydroxyethylamino)carbonylmethyleneoxyphenyl|-72,4-phenyl-2,4-pyrimidinediamine (K926506) pyrimidinediamine is obtained as a result reactions of 5-fluoro-Ma4-(3-hydroxyphenyl)-M2"-(33-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and 2"hydroxystylamine. РЖЖ/МС: retention time: 14.95 min; purity: 96 MS (small 414 (MNOI 7.3.512 5-fluoro-M4-(3-hydroxyphenyl)-192-(3-01- Analogous to the preparation of M4-(ethylenedioxyphenia)-5-fluoro-142-I34(M- methylamino )carbonylmethyleneoxyphenyl|- |methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, 5-fluoro-Ma-(3- 2,4-pyrimidinediamine (K926508U hydroxyphenyl)-2-(34(M-methylamino)carbonylmethyleneoxyphenyl|-7,4- pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M4-(3-hydroxyphenyl).M2-(3-ethoxy or methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and methylamine hydrochloride, IN NMR (0M50-d6:1 9.64 (5, 18), 9.58 (L5, 1NU, 8.15 (an, in 4.2 Sp), 7.95 (Bo, 1H), 7.25 (Ba, 2Y, 1: 6.6 Pi), 7 ... 15.66 min; purity: 9895; MS (m/z: 384 (MN). 7.3.513 5-fluoro-M4-13,4-(1,1,2,2-- Analogous to the preparation of M4-(3, 4-ethylenedioxyphenyl)-5-fluoro-M2-|3-0M- tetrafluoroethylenedioxy)phenylI-M2-I3-4(M- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimylindiamine, 5 fluoro-M4-13,4- me tylamino)carbonylmethyleneoxyphenyl|- | (1,1,2,2-tetrafluoroethylenedioxy)phenyl|-Mm2-|3-(M» 2,4-pyrimidinediamine (926732) methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidineliamine is obtained as a result of the reaction of 2-chloro-5- fluoro-M4-I3,4411,1,2,2-tetrafluoroethylenedioxy)phenyl-4-pyrimidinamine and methylamine hydrochloride. 1H NMR (YUM5O0-46): P 9.65 (5, 18), 9.37 (5, 1H), 8.164, 1H, 2- 3.6 Hn), 8.14 (4, 1H, 1-24 Hz), 7.97 (a, 1H, 15 4.8 Hz), 7.65 (44, 1H, 1-24 and 8.7 Hz), 7.41 (y, 1H, 2-93 Gy), 7.34 (6 EN. 12 2.4 Gy), 7.27 (y,

IN, 8, Gi), 7.13 (1, 12 8.1 Gu), 6.51 (44, 1H, 15 2.1 and 7.5 Hz), 4.36 (8, 2H), 2, 63 (0, ZN, 1- 4.8 Go); 19 E NMR (M 850-46): -25765 (redpi, 25), -25830 (repi, 2E), - 46309; LC/MS: retention time: 24.85 min; purity: 9599; MS (m/z): 497 (MN. 7.3.514 M4433,5-dimethyl-4-hydroxyphenyl)-5- Analogous to the preparation of M4-(ethylenedioxyphenyl)-5-fluoro-M2-|34(M- fluoro-M2- (3-0M-methylamino)carbonylmethyleneoxyphenia |-2.4-pyrimylindiamine, IM4-(3,5-dimethyl-4-morpholino)carbonylmethyleneoxyphenyl-|hydroxyphenyl)-5-fluoro-M2-0M-morpholinocarbonylmethyleneoxyphenyl)-2,4- 2, 4-pyrimidinediamine (940254) pyrimidinediamine is obtained as a result of the reaction M4-(3,5-dimethyl-4-hydroxyphenyl)" sem

M2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine and 7 | about morpholine. LC/MS: retention time: 18.38 min; purity: 9205; MS (m/z): 468 (MAU IN NMR (0М50-46): ГИ 9.20 (IN, 5), 9.10 (TIN, 5), 8.15 (IN, 5), 811 (IN, y, le 3.9 Hz), 7 zn, a, 12 8 Hn), 7.32 (ZH, t), 7.14 (NN, 6 78.1 Gy), 6.54 (IN, da, I-8 ,1 and 2.0 Gy), 4.77 (2H, 5), 3.64 (4H, to), 3.54-3.45 (AN, t), 2.24 (6H, 5). 7.3.515 M4-(3-tert-butyphenyl) M2-II3-(M- Analogous to the preparation of M4-(styrenedioxyphenyl)-5-fluoro- M2-13-(M-(Che)methylamino)carbonylmethyleneoxyphenyl)- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3-tert-5-fluoro-2,4-pyrimidinediamine (K940276) butyphenyl)-IM2-I3-(M-methylamino)carbonylmethyleneoxyphenyl-5-fluoro-2, 4-pyrimidinediamine is obtained as a result of the reaction of M4-(3-tert-butylphenyl)-M2-(3-ethoxycarbonylmethnleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine and methylamine hydrochloride. LC/MS: retention time: 22.90) min; purity: 9995; MS (m/z); h- 424 (MH; IN NMR (YUM50-46): 1 9.46 (IN, 5), 9.34 (IN, 5), 8.08 (1 H, y, 3- 3.9 Gy), 7.90 (IN, t), 7.30 (18, y, 3-8.1 Hz), 7.46 (18, t), 7.26 (1H, pt), 7.20 (2H, t), 7.10- urine 7.03 (2H, t), 6.47 (IN, a, 2: 8.1 Gy), 4.26 (2H, 5), 2.59 (ZH, y, 2- 4.5 Hz), 1 , 20 ZN, 8). ---- st so 7.3,516 A43-tert-butnylphenyl)-M2-134(M-2,3- Analogous to the preparation of M4-(ethylenedioxyphenyl)-5 "fluoro- M2-(3-(M.dihydroxypropylamino)carbonylmethylene | methylamino)carboniummethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3-tert»oxyphenyl|-5-fluoro-2,4-pyrimidinediamine butylphenyl)-Mm2-(3-4(M--2,3-dihydroxypropylamino)carbonimethyleneoxyphenyl |-5- (8940277) fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction M4-4(3-tert-butylphenyl)-

M2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-nirimidinediamine and 2,3-dihydroxypropylamine. LC/MS: retention time: 20.46 min; purity: 10005; "

MS (m/z: 484 (MN.K; IN NMR (OM50-46):1: 9.38 (1H, z), 9.29 (IN, 5), 8.20 (1H, 4, 1- 3.9 71), 8.00 (1H, d, 3- 8.3 Hn), 7.93 (1, 6, 7: 5.5 Hz), 7.60 (1H, p), 7.47 1 H, t), shsh 7.A1-7.17 (AN, tu, 6.59 (1 M, ad, 1-: 8.3 and 2 Hz), 3.43 (2H, 5), 3, 39 (Y, t), 35 (1H, c ti), 1.36 (OH, 5). h 7.-3.517 Mma-43,3-dihydroisobenfuran-1-mono-6- Similarly to the preparation of M4-(3, 4-Stylenedioxyphenyl)-5-fluoro-M2-1340MCh- and 1n)-M2-(3-7M--2,3-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, MA (3,3-dihydroxypronylamino)carbonylmethylene | dihydroisobenfuran-1-mono-b-iya)-M2-/3-0M-2,3-oxyphenyl| 5-fluoro-2,4-pyrimidinediamine dihydroxypropylamino)carbonylmethyleneoxyphenyl|-5-fluoro-2,4-pyrimidinediamine (K940293) is obtained as a result of the reaction M2-|34(ethoxycarbonylmethyleneoxy)phenyl|-M4-(3,3- dihydroisobenfuran-1 -mono-6-yl)-5-fluoro-2,4-pyrimidinediamine and 3-amino-1,2-(ee)propanediol. LC/MS: retention time: 13.92 min; purity: 9299; MS (m/z): 483 (MCU; IN NMR (0М50-66): 21 9.80 (1 НН, 5), 9.46 (IN, 5), 8.37-8.27 (2Н, t ), 8.21 with OH, 5) 7.96 PN, 3- 4.6Na), 7.24 (1, 4.15 9), 7.44 (IN, 5), 7.37 (IN, 8.159 Hyd), 7.23 (IN, 2-8 Hz), 6.60 (IN, yes, 7-7 and 3.75 035.49 (2H, 5), 4.46 (2H, 5), 3, 38 (AN, you), 3.2-3.1 1H, t). -th 0-5 (Se) 42) ko 60 b5

7.3.518 MA-(3,4-dimethoxyphenyl)-5-fluoro-M2-(3- Similar to the preparation of M4-(3,4-styrenedioxypheny)-5-fluoro-2-13-(M-(M-methylamino) carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, MA (3,4-methylamino)carboniummethyleneoxyphenyl- | dimethoxyphenyl)-5-fluoro-M2-|3-O-methylamino)carbonylmethyleneoxyphenylI-2,4- 2,A-pyrimidinediamine (KO26733) pyrimidinediamine is obtained as a result of the reaction of M4-(3,4-dimethoxyphenia)-5-fluoro-2-43--methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and methylamine hydrochloride. IN NMR (SOSIZU I 7.95 (9, 1H, 1- 3.6 Hz), 7.450 1H, 151.8 Hz), 7.21-7.17 (t, 2H), 7.05 (4d, TN , 1- 2.7 and 8.7 Hz), 6.96-6.90 (t, 2H), 6.87 (y, 1H, 1- 9.0 Hz) 6.72 ha, 1H, 2 24 Hn), 6.67-6.58 (t, IN), 6.52 (48, IN, 25 3.6 and 8.1 Hz), 4.39 (5, 2NI), 3.89 (5, ZN), 3 .78 (5, ZN), 2.90 (a, ZN, 12: 4.8 Hz); PH/MS: retention time: 17.09 min; purity: 9892; MS (m/z: 428 (MN). 7.3.519 M2-13-(M-2,3- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-I3-(1M-dihydroxypropylamino) carbonylmethylene | methylamino)kgerbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2 (3-(М-2,3- 7170 oxyphenyl|-М4-(3,4-dimethoxyphenyl)-5- dihydroxypropylamino)carbonylmethyleneoxyphenyl|-М4-(3, 4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (5926734) fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction M4-(3,4-dimethoxyphenyl)-5-fluoro-M2-(3--methoxycarbonylmethyleneoxyphenyl) -2,4-pyrimidinediamine and 3-amino-1,2-propanediol.IN NMR (Yum 50-46: 8.059, IN, 1-4.2 Hz), 7.38-7.34 (t, 2H), 7.31-7.26 (t, 2), 7.07 (0 IN, 1-8.4 Hn), 6.89 (y, IN, 1-8.7 Hn), 6.46 (44, 1H, 2-5 2.4 and 8.4 Hz), 4.36 (5, 28), 3.72 (in, ZNI), 3.68 (5, ZN), 3.32-3.24 ( t, ZN), 3.03 (40, IN, I» 6.9 and 13.5 Hn); 19 NMR (0M50-d6);:-46574;

LC/MS: retention time: 14.85 min; purity: 9495; MS (m/z): 488 (MN). 7-3.520 5-fluoro-M4-(3-methoxyphenyl)-M2-(3-(M- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-Mm2-(3-0M- methylamino)carbonylmethyleneoxyphenyl- methylamino)carbonylmethyleneoxyphenylI-2,4-pyrimidinediamine, 5-fluoro-M443-2,4-pyrimidinediamine (KO26738) methoxyphenyl)-M2-13-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-fluoro -M4-(3-methoxyphenyl)-M2-44-methoxycarbonylmothyloxyphenyl)-2,4-pyrimidiandismine and methylamine hydrochloride. РЧ/МС: duration of retention; 18.40 min.; purity; 9895;

MS (m/z)y: 398 (MN). 7.3.521 Mm2-13-0m-2,3- Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-13-0M-dihydroxypropylamino)carbonylmethylene | methylamino)carbonylmethyleneoxyphenyl l|-2,4-pyrimylindiamine, IM2 (3-(14-2,3-oxyphenyl|-5-fluoro-M4-(3-methoxyphenyl)- | dihydroxypropylamino)carbonylmethyleneoxyphenyl-5-fluoro-M443-methoxyphenial )- 2,d-pyrimidinediamine (926739) 2,4-pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenyl)-M4-(3-methoxyphenyl)-2,4-pyrimidinediamine and

Z-amino-1,2-propanediol. LC/MS: retention time: 16.66 min; purity: 9904;

MS (m/z); 458 (MN, p

Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(340h- He) fluoro-Mm2-I3-4(M-methylamino)carbonylmethyleneoxyphenyl-2,4-"pyrimidinedigmine, M4-43,5- dimethyl-4-piperazino)carbonylmethyleneoxyphenyl|- | hydroxyphenyl)-5-fluoro-M2-I3-(M-piperazino)carbonylmethyleneoxyphenyl|-2,4- 2,4-pyrimidineliamine (945140) pyrimidinediamine is obtained as a result of the reaction of M4-(3,5-dimethyl-4-hydroxyphenyl)- 5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and piperazine. IN NMR (СО3ОЙ):6 2.18 (5, 6), 2.72 (4, 1- 5.1 Gy, YAN), 3.32 (6 28), re) 3.520, 12 5.1 Gy, 2Н) , 4.55 (k, 2H), 6.56 (aa, 1-1.2, 2.4 and V.I. Gy, 1 H), 7.03 (444, 1-1.2, 1.8 and V.A Gd, 18), 7.11 (6 3258, Gu, 18), 7.20 (5, 2), 7.35, 1- 2.1 Hz, 1H), (e") 7.840, 1-5 3.9 Hz, 1H); I9E YM (282M Hn, СО300):5-168.78; LC/MS: retention time: 14.32 min; purity: 88.3725; MS (m/z): 467.06 (MIN). h-: 7.3.523 5-fluoro-M4-(3-hydroxyphenyl)-M2-(2-(M- Analogous to the preparation of M4-(ethylenedioxyphenyl)-5-fluoro-M2-Y3-0M-morpholinocarbonylbenzofuran-5-17| - methylamino)carbonylstyleneoxyphenyl-2,4-pyrimidinediamine, 5-fluoro-M4(3» Ha! 2,4-pyrimidinediamine (926488) tihydroxyphenyl)-m2-(2-(M-morpholino)carbonylbenzofuran-5-yl|-2 ,4-pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M4-(3-hydroxyphenyl)-M2-

Zo (2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and morpholine. IN NMR co (COzOrIs 89.35 1.5 Gy), 7.90 (4, 1H, 1 3.9 in), 7.44 (4, 2H, 1- 0.9 He), 7.28 (85, 1H ), 7.21 (B 1H, 12 2.4 Hz), 7.15 (0 IN, 3-7.5 Hyd), 7.98 (t, 180), 7.61 (6d, 1H, 1- 2 6.9 Sk), 3.8 (t, 4), 3.65 (t, 4H); RH/MIS: retention time: 17.21 min; purity: 8395; MS (m/z): 450 (MA). 7.3.524 5-fluoro-M4-(3-hydroxyphenyl)-M2-(2-(0M- Analogous to the preparation of M4-(ethylenedioxyphenyl)-5-fluoro-M2-(3-0M-" methylamino)carbonylbenzofuran-5-yl !- | methylamino)carbonylmethyleneoxyphenia|)-2,4-pyrimidinediamine, 5-fgor-MA-(3- 2.2-pyrimidinediamine (K926493) hydroxyphenyl)-M2-12-(M-methylamino)carbonylbenzofuran-5-yl|-2 ,4- shsh pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M4-(3-hydroxyphenyl)-M2-s(2-methoxycarbonylbenzofurav-5-yl)-2,4-pyrimidinediamine and methylamine hydrochloride. TIN NMR (SOZOYUKO 8.71 (y, IN, 3: 4.8 Hn), 8.00-7.92 (ti, 2), 7.56- "» 7.572 (t, 1), 7.44- 7.39 (t, 2H), 7.12 (t, 72), 6.69 (Bai, IN), 2.96 and 2.94 (28, ZN). n 7.3.525 5-fluoro-M4- (3-hydroxyphenyl)-M2-(2-(0M- Analogous to the preparation of M4-(ethylenedioxyphenyl)-5-fluoro-M2-13-(M- x methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-M4 -(3- hydroxyethylamino)carbonylbenzofuran-| as a result of the reaction of 5-fluoro-My-(3-hydroxyphenyl)-M2-(ee) (2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimylidenediamine and 2-hydroxyethylamine.

IN NMR (SOSIZU OO 8.18 (9, 1H, 32 1.8 i), 7.80 (b5, EN), 7.60 (t, EN), 7.34-7.16 (t,

ZNO, 71097, 1H, 8.4 Hz), 6.85 (vd, 1), 6.62 (yd, EN, 2» 1.5 and 8.1 Hz), 3.70 (1, 2H, ko 1-48 Hz), 3.52 (65 7Н, 1-4.0 Ha); PH/MS: retention time: 14.49 min; purity: 9795; MC (m): 424 (МН, - 7.3.526 5-fluoro-М4-(3-hydroxyphenyl)-М2-(2-/М- Analogously to the preparation of М4-(ethylenedioxyphenyl)-5-fluoro-М2-|340М- NzhzhtTTnnt now (Se) 42) ko 60 b5 piperazino)carbonylbenzofuran-5-yl)-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-M4-(3-2,4-pyrimidinediamine (8926500) hydroxyphenyl)- M2-(2-(M-piperazino)carbonylbenzofuran-5-yl1-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M4-(3-hydroxyphenyl)- M2-(2-methoxycarbonylbenzofuran-5-yl)-2 . 725-706 (t, AN). 6.59 (t, 1H), 3.80 (t, 4H), 2.95 (t, 3H); LC/MS: retention time: 12.97 min; purity: 7995; MS (m/z): 449 (MN.K). 7.3.527 3-cyano-M4-(3-hydroxyphenyl)-M2-I440M- | Similar to the preparation of M44(3,4-ethylenedioxyphenyl)-5-fluoro -M2-(3-M-methylamino)carbonylmethyleneoxyphenyl- | methylaminocarbonylmethyleneoxyphenyl)-2,4-ktyrimidinediamine, 5-cyano-M4-(3-2,4-pyrimijudiamine (K925844) tihydroxyf enyl)-M2-(44-M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-dnano-M2-(4-ethoxycarbonylmethyleneoxyphenyl)-4-(3-hydroxyphenyl)-2,4-pyrimidinediamine and methylamine hydrochloride. PH/MS: retention time: 18.83 min; purity: 9695;

Me (m/z): 391 (MNE. 7.3.528 5-cnano-M4-1440M- Analogous to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-13-(M-cyclopropylmethylamino)carbonylmethyl o | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 5-cygno-M4-14-(M-enoxyphenia|-M243-hydroxyphenyl)-2,4- | pyclopropylmethylamino)carbonylmethyleneoxyphenia|-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (5925845) pyrimidinediamine is obtained as a result of resection of 5-cyano-M2-(4-ethoxycarbonylmethyleneoxyphenyl)-M4-(3-thihydroxyphenyl)-2,4- pyrimidinediamine and cyclopropylmethylamine. RH/MIS: retention time: 22.47 min; purity: 10095;

MS (m/z: 431 (MN). 7.3.529 5-cnano-M44(3-hydroxyphenyl)-M2-(4-(M- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro- M2-I134(0M-28-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, 5-cyano-Ma-(3-dihydroxypropylamino)carbonylmethylene|hydroxyphenyl)-m2-14-(M--2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl| - oxyphenyl)|-2,4-pyrimidinediamine 2,4-pyrimidinediamine is obtained as a result of the reaction of 5-nnano-M2-(4- (8925846) ethoxycarbonylmethyleneoxyphenyl)-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine and 2, 3-dihydroxypropylamine. LC/MS: retention time: 15.84 min; purity: 10095; MS (m/zu: 451 (MN). 7.3.530 5"fluoro-m2-134(M- Analogously to the preparation of M4-(3 ,4-ethylenedioxyphenyl)-5-fluoro-M2-13-4(M-methylamino)carbonylmethyleneoxyphenyl-

M4-(3-trifluoromethylphenyl)-2,4-methylamino)carbonylmethyleneoxyphenyl))-44-(3-trifluoromethylphenyl)-2,4-pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of M2-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-Mma4 -(3-trifluoromethylphenyl)-2,4-s pyrimylinamine and methylamine hydrochloride. LC/LMS: retention time: 21.98 min, purity: 8695, MS (m/z): 436 (MNK). o 7.3.531 M4-14-(4,5-dichloro-1H-imidazole-I-- Analogous to the preparation of MA-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-(M-ilphenia)| -5-fluoro-M2-|3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-14-(4,5-dichloro-methylamino)carbonylmethyleneoxyphenyl|- | 1H-imidazol-1-ylphenyl) | -5-Fluor M2-(3-IM-methylamino)carbonylmethylene oxyphenyl|- 2,4-pyrimidinediamine (K926812) 2,4-pyrimidinediamine is obtained as a result of the reaction M-4-(44(4,5-dichloro-1 H- (se) imidazol-1-ylphenyl)-5-fluoro-M2-(3-stoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and methylamine hydrochloride. LC/MS: retention time: F 21.02 min, purity: 10095, MS (m/z): 502 (MN). 7.3.532 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-YIM2- | Analogous to the preparation of M4-(3,4-ethylenedioxyphenia)-5-fluoro-M2-(3-(0-chche (2-(M-methylaminocarbonylindop-7-yl)» methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamic, M4 -(3,4-2,4-pyridinediamine (KU26815) ethylenedioxyphenyl)-5-fluoro-M2-(2-(M--methylaminocarbonylindol-7-yl)-2,4-pyridinediamine is obtained as a result of the reaction M2-(3 - i. ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-M4-(3-trifluorophenyl)-2,4-pyrimidinamine and methinamine hydrochloride. LC/MS: retention time: 17.97 (ee) min, purity: 9750, MS (m/ z): 435 (МН. 7.3.533 M44(3,ethylenedioxyphenyl)-5-fluoro-im2- Analogously to the preparation of 1M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-I340M-

IZ (M. methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3,4- morpholino)arcarbonylmethyleneoxyphenyl|- | ethylenedioxyphenyl)-5-fluoro-m2-(34XM-morpholino)carbonylmethyleneoxyphenyl|-2,4-2,4-pyrimidinediamine (K926484y pyrimidinediamine is obtained as a result of the reaction M2-(3-" ethoxycarbonylmethyleneoxyphenyl)-M4-(3,4-styrenedioxyphenyl )-5-fluoro-2,4-pyrimidinediamine and morpholine. IN NMR (SOCI3): C 7.94 (B5, IN), 7.35 (1, 1H, 4- shsh 2.4 g), 7.24 (t, 1), 7.196 1H, - 8.1 Si), 7.10 (Bad, IN, 3- 6.9 Hn), 6.95 (t, 2H), c 6.854, 1H,3- 8, 1 Hz), 6.94 (5, 1NU, 5.58 (ai, IN, 1- 1.8 and 2.8 Hz), 5.64 (5.28), 5.27

Fe, ANI), 3.62 (t, NI), 3.55 (ta, 4H); PH/MS: retention time: 18.45 min; h » purity: 10095; MS (m/z): 482 (MNK. p. 7.3.534 Ma4-(3,a-ethylenedioxyphenyl)-5-fluoro-M2- | Similar to the preparation of IM4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2 -13-(0h» (2-(M-morpholino)carbonylbenzofuran-methylamino)carbonylmethyleneoxyphenyl/|-2,4-pyrimidinediamine, M4-(3,4-5-ip|-2,4-pyrimidinediamine (K926492) ethylenedioxyphenyl) -5-fluoro-M2-(2-(M-morpholino)carbonylbenzofuron-5-yl)-2,4- pyrimidinediamine is obtained as a result of the reaction of M4-(3,4-ethylenedioxyphenyl)-5- (o c fluoro-M2- (2-- methoxycarbonylbenzofuron-5-yl)-2,4-pyrimidinliamive and morpholine.

NMR (0M5O-46):1 9.27 (5, 1H), 9.17 (in, 1H5), 8.14 (80, 1H, 72 2.4 Hz), 8.054, 1H, with 1- 5.6 Hz), 7.58-7.46 (t, 2H), 7.27 (t, IN), 7.15 (84, 1H, 12: 2.4 and 9 Gk), 6.80 Ohm,

IN", 4.24 (5, 4H)), 3.80-3.45 (t, 88); PH/MS: retention time: 19.97 min; purity: 769 MS (m/z): 492 (MN). - 7.3.535 ma43,4-ethylenedioxyphenyl)-5-fluoro-M7- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|344M- «se 50 12-(M-methylamino)carbonylbenzofuran- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3,4-42) ko 60 b5

5-yl|-2,4-pyrimidinediamine (926496) stylenedioxyphenyl)-5-fluoro-M2-(2-(1M-methylamino)carbonylbenzofuran-5-ylI-2,4-pyrimidinediamine is obtained as a result of reaction M4-(3, 4-ethylenedioxyphenyl)-5-fluoro-M2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and methylamine hydrochloride. 1H, 2- 3.3 Hz), 7.426, 2H, I1- 12), 7.35 (5, EN), 7.29 (4, 1H, 1-24 Hz), 6.99 (yes, IN, 1- 3.3 and 8.7 Hz), 6.78 (4, 1H, 2- 8.7 Gy), 4.24 (z, 4NI), 2.94 (5, ZNU; RH/MS: duration retention: 18.05 min; purity: 9995; MS (m/z): 436 (MNK). 7.3.536 MI-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(3, 4-ethylenedioxyphenyl)-5-fluoro-M2-(3-0M-

M methylamino) carbonyl methyleneoxyphenyl I-7,4-pyrimidinediamine, M4-(3,4. hydroxyethylamino) carbonyl benzofuran- | ethylenedioxyphenyl)-5-fluoro-142-(2-0-2-hydroxyethylamino)carbonylbenzofuran-5-5-yl1-2.4-pyrimidinediamine (K926498) yl1-2,4-pyrimidinediamine is obtained as a result of the reaction M4-(3,4 - ethylenedioxyphenyl)-5-fluoro-1M2-(2-methoxycarboniabenzofuran-5-yl)-2,4-pyrimidinediamine and 2-hydroxyethylamine. IN NMR (SPZOI) 01 8.07 (a, 1H, 2-12

Gy), 7.86 (0, IN, 2: 3.9 Hn), 7.43 (4, 2H, I- 1.5 Gy), 7.38 (5.18), 7.29a, 1H, 2:24

Em), 6.98 (440, 1H, 322.1 and 9 Gu), 6.78 (a, 1H, 3-8.7 Hz), 4.23 (5, 4H), 3.72 (0 2H , 1-5.7 Hz), 3.53 (1, 2H, 1-5 6.0 Hz); LC/MS: retention time: 16.21 min; purity: 9795; MS (m/z): 466 (MN). 7.3.537 M4-3,4-Stylenelioxyphenyl)-5-fluoro-YM2- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-1340M- (2-(M-piperazino)carbonylbenzofuran-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4-(3,4-5-yl |-2,4-pyrimidinediamine (K926499) ethylenedioxyphenyl)-5-fluoro-M2-(2-(M-piperazino)carbonylbenzofuran-5-1lI-2,4-pyrimidinediamine is obtained as a result of the reaction M4-(3,4-ethylenedioxyphenyl )-5-fluoro-M2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and piperazine,

IN NMR (0M50-46: 17 9.26 (5, NN), 9.16 (5, IN), 8.12 (ai, 1H, 7: 1.8 Gy), 8.044, IN, 1-36 Hz ) 7.49(y0, 2), 7.30(4.1H, 12.4 Gy), 7.205, 18), 7.15 (644, 1H, 1-3 Hz), 6.79 (y, IN, 12 8.7 Hz), 4.22 (5, 4H), 2.48 (5, ЗН); РЧ/МС: duration of seizure: 14.61 min; purity: 9495; MS (m/z): 491 (MN). 7.3.538 Ma4-(3,4-styrenedioxyphenyl)-5-fluoro-M2- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-I|3-41h-

IZAM- methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4 (3,44 piperazino)carbonylmethyleneoxyphenyl|- | stylenedioxyphenyl)- 5-fluoro-M2-I3-(M-piperazino)carbonylmethyleneoxyphenyl|-2,4- 2,d-pyrimylindigmine (2926503) pyrimidinediamine is obtained as a result of the reaction of M4-(3,4-ethylenedioxyphenyl)-5- fluoro- M2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and piperazine. YIN YAM (SUZOGU): 2 9.14 (b5, 2), 8.04 (4, 3.6 Hz), 7.32-7.20 (t, 4H), 706(BIN, IV g), 6b .79 (a, a, 1 H, 1-9 Hn), 6.43 (LB, 1H, 22 99 Hz), 4.64 (5, 2H), 4.20 (5, 4H), 3.29 (t, 4H), 2.59 (t, 4H); LC/MS: retention time: 14.92 min; sem purity: 9935; MS (m/z)y; 481 (I HAVE). 7.3.539 Ma-(3,4-styrenedioxyphenyl)-3-fluoro-M2- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-I3-0M-

I3-(m-2-hydroxy-1,1-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4-4(3,4-dimethylethylamino)carboxymethyleneoxy | ethylenedioxyphenyl)-5-fluoro-M2-(3-(0M4-2-hydroxy-1,1-phenyl|2,4-pyrimidinediamine (K926764) dimethylethylamino)carboxymethyleneoxy |phenyl|-2,4-pyrimidinediamine is obtained as a result of reaction M4 -(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(Che)methoxycarbonylmethyleneoxyphenyl)-7,4-pyrimidineliamine and 2-amino-7-methylpropanol. IN NMR (SOSIZKP 7.95 (4, 1Н, 122.7 Hz), 7.47 0, 1H, 1-24 b

Gi), 7.20 (6 IN, I1- 8.1 Hz), 7.03 (49, 19, 2: 1.2 and 8.1 Hz), 6.98 (da, 18, 32: Z and 8.2

Gi), 6.93 (5, 1H)), 6.84 (9, 1H,, 1-x 8.7 Hz), 6.66 (d, 1H, 7-3 Hz), 6.57 (5 , 180), 6.53 (n, 1H), 4.65 (tp, 1H), 4.39 (5, 2H), 4.28 (5, 4H), 3.63 (4, 2H, 3- 5.7 Hz), 1.31 (8, 6H); or

PH/MS: retention time: 19.19 min; purity: 8995; MS (m/z): 484 (MN). M2 -|34(M-

C5 phenyl)-M4-(3,4-ethylenedioxyphenyl)-5-cyclohexylamino)carbonylmethyleneoxyphenyl|-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-(ee) fluoro-2,4-pyrimylidenediamine (KU26765) 2, 4-pyrimidinediamine is obtained as a result of the reaction of M4-(3,4-ethylenedioxyphenin)-5-for-M2-|3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and cyclohexylamine. IN YAM (SOSIZ): О 7.94 (y, 18, 1: 3.3 Gi), 741 (NN, 1" 24

Gi), 7.28 (4.1H, 2-24 Hz), 7.20 (B1H, 15 7.5 Hz), 7.04 (46, 1H, 34- 1.2 and 8.1 Go), 6 .95 (t, 2H), 6.85 (d, 1H, 3-8.7 Hz), 6.68 (d, 1H, 1- 3.0 Hn), 6.53 (ai, 1H, )- 2.4 and « 8.4 Hz), 6.45 (Ba, 1H, 3: 8.1 Gy), 4.43 (5, 2H), 4.24 (v, 44), 3.85 (t , 1H), 1.90 (t, 2H), 1.75-1.55 (t, 2), 1.45-1.05 (t, 6H); LC/MS: retention time: 23.70 min; purity: 9795; MS (m/z): 494 (MN). shsh c 7.3.541 Ма4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2» Similar to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-И340М- (3-(М-methyl-М -(2-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, М4-(3,4-"z hydroxystil)aminocarbonylmethyleneoxy | ethylenedioxyphenyl)-5-fluoro-M2-|3-II-methyl-М-(2- p phenyl|-2,A-pyrimidinediamine (5926766) hydroxystyl)amino|carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction M4A-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-13-methoxycarbonylmethyleneoxyphenyl)-2, 4-pyrimidinediamine and MM-methyl-M-2- hydroxyethylamine. 1H NMR (SOSIS): 7 7.93 (0, 1H, 7: C Gy), 7.92 (Bv, 1H), 7.35 (6 1H ,-72.4 Hz), 7.18 (t, IN), 7.06 (ad, TN, 1-1.2 and 8.7 Gy), 6.97 (1, IN, 1-24 Gy) , (ee) 6.94 (t, 1), 6.85 (4, IN, I 8.7 Gy). 6.79 (4, 1H)), 6.59 (440, 1, 2- 1.8 and V.I Gi), 4.66 (5, 2H), 4.28 (5, 4NI), 3.79 (b, 2H, 1- 5.4 Hz), 3.56 (i, ЗН, 3- 5.4 Hz), 3.10 (in, ZN); ke RH/MS: retention time: 16.54 min; purity: 9755; MS (m/z); 470 (MNE), 7.3.542 shma4(3 ,4-ethylenedio xyphenyl)-5-fluoro-IIM2- | Analogous to the preparation of M4-(3,4-etipenedioxyphenia)-5-fluoro-M2-I3-(M- rak (M. methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, IM4-(3,4-homopiperazino)carbonylbenzofuran-5 - | ethylenedioxyphenyl)-5-fluoro-m2-(2-homopiperazinecarbonylbenzofuran-5-1l)-2,4- (Ce) 42) ko 60 b5 in) MA-pyrimidinediamine (926767) pyrimidinediamine is obtained as a result of the reaction M4-(3 ,4-ethylenedioxyphenyl)-5-fluoro-M2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinliamine and homopiperazine. 1H NMR (PM5O-46): P 9.27 (5, 1H), 9.17 (4, IN, 7: 1.2 Hz), 8.14 (5, IN), 85.05 (y, IN , 3 3.6 Hz), 7.54-7.46 (t, 2Н), 7.30 (4, IN, 2- 2.4 Hz), 7.24 (5, 1НУ7.17(40.1Н , 7-24 and 8.7 Gy), 6.80 (8, 1H, 3 8.7 Hz), 4.22 (5, 4H), 3.79 (t, 2H), 3.65 (t, 2H), 3.01 (t, 2H), 2.89 (it, 2H), 1.90 (t, IN), 1.80 (t, 1H); 19 E YAME (OM50-ab):-46687 ; LC/MS: retention time: 14.99 min; purity: 7790; MS (m/z): 505 (MNU. 7-3.543 M4-(3,4-ethylenedioxyphenyl)-M2-13-0M,M- | Similar to the preparation of M4A-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-04-dimethylamino)carbonylmethyleneoxyphene | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3,4- pi -5-fluoro -2,4-pyrimidinediamine ethylenedioxyphenyl)-M2-(3-(M,M-dimethylamino)carbonylmethyleneoxyphenylI-5-fluoro- (8925755) 2,4-pyrimidinediamine is obtained as a result of reaction M44(3,4-ethyphendioxyphenyl)-5- fluoro-M2-4(3-methoxycarboniamethyleneoxyphenyl)-2,4-pyrimidinediamine and MM-dimethylamine hydrochloride. 18 NMR (OM5O-46):0 9.16 (4, 1H, her 1.2 Gy), 9, 15 (5, 1NU, 8.04 (a, 1 H), 7: 5.6 Cy), 7.30-7.21 (t, 4H), 7.06 (her, IN, 3- 9Nag), 6.78 (4, 1H, 1- 9Hg), 6.43 (t, IN), 4.65 (5, 2H), 4.21 (z, 4NI), 2.94 (in, ZN), 2.82 (z, ZNU; PH/MS: retention time: 18.70 min; purity: 8395; MS (m/z); 440 (MNK). 7.3.544 142-(3-M,M-bis-(2- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-40M- hydroxyethylamino)|)carbonylmethyleneoxy| -2.4-pyrimidinediamine, M2-|3-HMM-bis-(2-phenyl-M4-(3,4-ethylenedioxyphenyl)-5-tihydroxystylamino)|carbonylmethyleneoxyphenyl|-M4-(3,4-ethylenedioxyphenyl)-5- fluoro -2,4-pyrimidinediamine (K926781) U fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenia)-2,4-pyrimidineliamine and M .M-bis(hydroxystil)amine. IN NMR (СО3012): 0 7.86 (4, 1Н, 1-3.6 Hz), 7.25 (t, 28), 7.17-7.03 (lo, ЗН), 6.78 (y , 1H, 1-9), 6.58 (84, 1H), 4.80 (5, 2H), 4.23 (5, 4H), 3.71 (i, AN, 1- 4.8 Go) , 3.53 (i, 2H, 12: 5H), 3.49 i, ЗН, I- 5.4 Ha); RHLMS: retention time: 10.25 min; purity: 9495; MS (m/z); 500 (МН. 7.3.545 М2-И340М-73) and in a method similar to the preparation of MA-(3,4-ethylenedioxyphenyl)-5-fluoro-42-(3-(M-dihydroxypropylamivo)carbonylmethylene | methylamino)carbonylmethyleneoxyphenyl -2,4-pyrimidinediamine, M2-|3-(04-2,3- oxyphenia|-M4-4(3,4-ethylenedioxyphenyl)- | dihydroxypropylamino)carbonylmethyleneoxyphenyl-M4-(3,4 ethylenedioxyphenyl)-5-

C-fluoro-2,4-pyrimidinediamine (KU26782) fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and 2,3-dihydroxypropylamine. 18 NMR (SOZOBI: SI 7.86 (1, 1-42gy4)737(iH, I 8 g), 7.244, 1H, 3-24 Hz), 7.14 (t, 2H), 7.09 (ad, 1H, 1-2.4 and 9 Hz), 6.78 (0, 1H, /- 8.7 Gy), 6.59 (td, TN), 4.39 (5, 2H), 4.22 (in, 4H) . ,3- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(341M-digyloxypropylamino)carbonylbenzoph | methylamino)carbonylmethyleneoxyphenyl)-24-pyrimidinediamine, M2-(2-(M4-2,3- ran -5-yl|M4-(3,4-ethylenedioxyphenyl)-5-|dihydroxypropylamino)carbonylbenzofuran-5-yl)-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (K926783) fluoro -2,4-pyrimidinediamine is obtained as a result of the reaction of IM4-(3,4-(Che)ethylenedioxyphenyl)-5-fluoro-M2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and 2,3-dihydroxypropylamine IN YAMA (СО3О0У:О 7.864, zn Hz), 7.355 IN, 1-1, Hyd, 7.24 (4, IN, 7- With Gy), 7.15 (t, 28), 7.07 (а, 1Н, 1 - (o) 2.1 ha 8.7 Hz), 6.78 (4, 1H, 7- 8.7 Hz), 6.59 (ha , IN), 4.40 9e, IN), 4.23 (5, 45), 4.03 y,

IN, 12 5.7 Hz), 3.67 (4, 2H, 3.6 Gy), 3.65 (4, 2H, 3- 4.2 Hz); ISE NMR (SUZOYU) - h: 41578; LC/MS: retention time: 15.72 min; purity: 9992; MS (m/z): 486 (МНы. сч 7.3.547 М2-13-(М-1,3-dihydroxy-2- Similar to pritotium M4-(3,4-ethylenedioxyphenyl)-5-fluoro-м2-134( M-propylamino)carbonylmethyleneoxyphenyl) | methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M2-13-(M--1,3- co -Ma4-(3,4-styrenedioxyphenyl)-5-fluoro-2,4- | diezdroxy-2-propylamino)carbonylmethyleneoxyphenyl)-M4-(3,4-ethylenedioxyphenyl)-pyrimidinediamine (8926784) 5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(3,4-ethylenedioxyphenyl)-5-fluoro -M2-(3-methoxycarbonylmethylenedioxyphenyl)-2,4-pyrimidinediamine and 2-amino-1,3-propanediol. IN NMR(CONSTELLATION 8.08 (59, IN), 7.86 (b5, 1), 7.44 (8, 2), 7.39 (z, IN), 7.29 (0, IN, 12 2 ,4 Gi), 6.97 (04, IN, 12 2.4 and 8.7 Hz), 6.78 (а, ТН,, ne» 8.7 Hz), 4.24 (5, 4Н), 3.84 (t, 1H), 3.56 (t, 2H)), 3.44 (t, « 2NU; PH/MS: retention time: 15.63 min; purity: 9795; MS (m/z) : 496 (МН.). 40. 73548 М2-12-(М-1,3 dihydroxy-2- Analogous to the preparation of М4-(3,4-styrenedioxyphenyl)-5-fluoro-М2-(3-04- - with propylamino )carbonylbenzofuran-5-yl)-|methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamic, M2-(240М4-1,3-

M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-| dihydroxy-2-propylamino)carbonylbenzofuran-5-1l|-M4-(3,4-styrenedioxyphenyl)-5-p pyrimidinediamine (5926785) fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(3,4- and P .ethylenedioxyphenyl)-5-fluoro-M2-42-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine and 2-amino-1,3-propanediol. TV NMR (SOZOYUKO 8.08 (IN, 1 1.8 Sv), 7.86 (y, IN, 7- 3.9 Hz), 7.45 (v, 28), 7.41 (5, 1H) , 7.29 (9, IN, 5-24 Hz), 6.97 (84, 1H, 1-3 and 8.7 Hz), 6.77 (4, 1H, )-e 8.7 Gy), 4.24 (5, 4H), 4.19 (0, 1H, 1-2 5.7 Hz), 3.75 (a, 4H, 1- 5.4 Hz; I9E YAM? (SOZOB);-47745 ; LC/MS: retention time: (o e | 15.09 min, purity: 9795; MS (m/z): 496 (Mn. 7.3.549 Ma-(3-chloro-4-hydroxy-5-methylphenyl) -5- | Analogous to the preparation of M4-(ethylenedioxyphenyl)-5-fluoro-M2-13-(0M- co fluoro-m2-13-(M- methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidoquindiamine, M4A-(3-chloro- 4- meorfolino)carbonylmethyleneoxyphenia|- | hydroxy-5-methylphenyl)-z-fluoro-M2-(3-(M-morpholino)carbonylmethyleneoxyphenyl|- - 2,A-pyrimidinediamine (KU40265) 2,4-pyrimidinediamine is obtained as a result of the reaction m4- (3-chloro-4-hydroxy-5-(Ce) 42) co 60 b5 methylphenyl)-M2-(3-htoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine and morpholine. LC/MS: retention time: 18 ,66 min; purity: 9296; MS (m/z): 487 (M), 489 (MH); IN NMR (0М50-46): 9.28 (2Н, 5), 9.01 (1H, 5), 8.17 (IN, d, 4- 3.6 Hz), 7.65 (18, b, 2- 2.4 Hz), 7.5 (an, a, 3-27 Hz ), 7.42 (IN, a, 1-66 GI), 7.29 1H, 5), 7.18 (IN, 7e 8.1 Gy), 6.57 (IN, y, 12 6.6 and 2.2 Gy), 4.79 (2H, 5), 3.67 (AN, t), 3.52 (4H, t), 2.29 (ZH, 5). 7.3.550 m44(3,5-dichloro-4-hydroxyphenyl)-2-14-(3,5-Dichlorophenyl-4-hydroxy)-YM2-(3-stoxycarbonylmethyleneoxyphenyl)-5-phthor-fluoro-M2-(3 -(M-7,4-pyrimidinediamine (0.5 g, 1.1 mmol) is dissolved in EUN: morpholine (4 ml: 4 ml), morpholino)carbonylmethyleneoxyphenyl|- | and then the mixture is heated in a reflux flask for ! day 2,4-pyrimidinediamine (K950187) (oil bath temperature -100°C). The mixture is cooled to 22°C, dissolved in water and brine, filtered, and then dried under reduced pressure to obtain M4-(3,5-dichloro-4-hydroxyphenyl) )-5-fluoro-M2-I3-4(M-morpholino)carbonylmethyleneoxyphenyl)|-2,4-pyrimidinediamine, 1 N АМ? (OM5O0- 46):5 9.35 (5, IN), 9.22 (5, 1H), 8.09 (d, IN, 1- 3.6 Gy), 7.94 (t, 1H), 7.75 (t, 1H), 7.27 (t, 1H), 7.18 (t, IN), 7.12 1H, I- 8.4 Hn), 6.44 (t, 1H), 4.64 (5, 2H), 3.39 (t, "A, 2.68 (t, 4NU, RH/MS purity: 92.07, MS (m/zu: 507.89 (Mk, 100)). 7.3.551 М4-(3,5-dichloro-4-thihydroxyphenyl)-5- Similar to the preparation of IM4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-m2-(34(М- fluoro-М2-(34( M» morpholino)carbonylmethyleneoxyphenyl)-2,4-pyrizidinediamine, M4 (3,5-dichloro-4-piperazino)carbonylmethyleneoxyphenylI- | hydroxyphenyl)-5-fluoro-M2-(13-(M4-piperazino)carbonylmethyleneoxyphenyl|-2, 4- 2,a-pyrimidinediamine (KO501858) pyrimidinediamine is obtained as a result of the reaction M4-(3,5-dichloro-4-hydroxyphenyl)"

of M2-(3-stoxycarbonylmethyleneoxyphenyl)-3-fluoro-2,4-pyrimidinediamine and piperazine. LC/MS: retention time: 15.26 h; purity: 88.595; MS (m/z); 506.89 (МН), 7.3.552 142-(3,4-ethylenedioxyphenyl)-5-fluoro-Ma- | Similarly to the preparation of M4-(ethylenedioxyphenyl)-5-fluoro-M2-134(M-

IZ methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M2-(3,4-methylamino)carbonylmethyleneoxyphenyl|- | ethylenedioxyphenyl)-5-fluoro-M4-(34(7M-methylamino)carbonylmethyleneoxyphenyl|-2,4- 2,4-pyrimidinediamine (KU26776) pyrimidinediamine is obtained as a result of the reaction M4-(3-ethoxycarbonylmethyleneoxyphenyl)-IM2-(3,4 -etipendioxyphenia)-5-fluoro-2,4-pyrimidinediamine and methylamine hydrochloride. LC/MS: retention time: 16.94 min; purity: 7395; MS (m/z)y: 426 (MH). 7.3.553 M2 -(3,4-etiphenedioxyphenyl)-5-fluoro-M4- | Similar to the preparation of 5-fluoro-M4-(3-tihydroxyphenyl)-M2(4- (8-methylaminocarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine, M2-(3 ,4- methylaminocarbonylmethyleneoxyphenia)- | stylenedioxyphenyl)-5-fluoro-M4-(4-methylaminocarbonylmethyleneoxyphenyl)-2,4-urea 2.4-pyrimidinediamine (5945173) pyrimidinediamine is obtained as a result of the reaction M444-pianomethyleneoxyphenyl)-

M2-(3,a-ethylenedioxyphenial)-5-fluoro-2,4-pyrimidinediamine and methylamine (5) hydrochloride. IN NMR (apeton-4d6): 5 2.80 (4, ZN), 4.21-4.28 (t, 4NI), 4.47 (5, 2H), 6.71 (4, 18.7 Hz , 1H), 6.96 (y, 72: 9.0 Hz, 2NO), 7.06 (yes, 1- 2.7 and 9.0 Gy, 1H), 7.41 (6, 1-24 Hz , 1H), 7.74 (4.1-90 Sn, 2H)), 7.93 (0.1-3.6 Hz, 1H), 8.20 (g, IN, MAYA), 8.41 ( Be, IN, MN; 197 NMR (282M HC, acetone-46): 0-169.05; LC/MS: duration of retention: 17.47 ha; purity; 95.99; MS (m/zu: 425.89 (МН). (Те) 7.3.554 М2-14-(2-М,М- Analogously to the preparation of ИМ4-(3,4-styrenedioxyphenyl)-5-fluoro-ИМ2-(3» dimethylaminoethyl)oxyphenyl|-5-fluoro -M4- | hydroxyphenyl)-2,4-pyrimidineliamine, M2 14-22-M,M-dimethylaminostil)oxyphenyl|- (e")

I13-(M-5-fluoro-M4-I3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine methylamino)carbonylmethyleneoxyphenyl|- | are obtained as a result of the reaction of M2-chloro-5-fluoro-M4-(3-(0M» 2,4-pyrimidcndiamine (K909253) methylamino)carbonylmethyleneoxyphenyl|-4-pyrimidinamine and 4-(2-M,M- h-dimethylaminoethyl) oxyaniline. IN NMR (SOZOUI:P 8.0 (0, 19 3-4 Ha), 7.42 (t, 2H), 7.24 (t, 2H), 7.05 (t, NU, 6.85 (t, 1H), 4.39 (5, 2H), 4.30 (t, 2H0), 3.66 (t, He 2H), 3.04 (5, 6H), 2.83 (5, ЗН ); LC/MS: retention time: 14.0 min; purity: 9655; ME (m/z): 455 (MN). so 7.3.555 M241,4-benzoxazin-b-yl)-5-fluoro-M4 Similarly, to obtain M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(M-hydroxyphenyl)-2,4-pyrimidinediamine, M2 (1,4-benzoxazin-b-1l) -5-fluoro-M4-13-0h» methamino)carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained in 2,4-pyrimidinediamine (K909247) as a result of the reaction M2-chloro-5-fluoro-M4-( 3-(0M-methylamino)carbonylmethyleneoxyphenyl|-4-pyrimidinamine and b-amino--1,4-" benzoxazine. TN(0M50-46):0 8.0 (y, 1H), 7.6 (t, 1 NU, 7.42 (t, 1H), 7.20 (t, 1H), 6.95 (t, 1H), 6.76 (t, 1H), 6.56 (t, 1H), 4.43 (8, 2H), 4.05 (t, 2H), 3.25 (v. ZNU, 3.13 - (t,2NU, LC/MS: te: 17.67 min; MS (mi/z): 425 (MN). s 7.3.556 M2-(4-dihydrobenzofuranyl)-5-fluoro- M4- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-h 134M-hydroxyphenyl)-2,4-pyrimidinediamine, M2 (4-dihydrobenzofuranyl)-5-fluoro-Ma-( 3- and R. methylamino)carbonylmethyleneoxyphenyl-|(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinedigmine is obtained in 2 Alirimylindimine (2909249) as a result of the reaction M2-chloro-5-fluoro-ma-13-(M-methylamino)carbonylmethyleneoxyphenyl |-4-chirymylinamine and 5-amino-2,3-dihydrobenzofuran. IN NMR (PM5O-y6):0 8.09 (4, 1H), 8.00 (t, IN), 7.42 (t, 2H ), 7.05 (tp, IN), 6.96 (t, IN), 6.75 (t, 1H)), 6.58 (t, IN), 4.53 (tb, 2H), 4, 25 (5, (ee) 2H), 3.15 (t, 28), 2770 (t, ZN); PH/MS: retention time: 19.24 min.; MS (m/z): a (МН. ко 7.3.557 12-(3-tert-butylphenia)-М4-(3-(М- Analogous to the preparation of М4-(styrenedioxyphenyl)-5-fluoro-М2-13-4 (M-methylamino)carbonylmethyleneoxyphenyl-|meylamino)carbonylethyleneoxyphenyl-2,4-pyrimidinediamine, reaction M2-(3-tert»-5-fluoro-2,4-pyrimidinediamine (K940267) butyphenyl)-M4-(3- ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine with methylamine hydrochloride leads to the formation of M2-(3-tert-butylphenyl)-M4. SHO (Ce) 42)

F) ko 60 b5

I3-(x methylamino)carbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.

RHLMS: length of stay; 22.22 min; purity: 9795; MS (m/zu; 424 (MN; IN

NMR(SOSIS) OO 7.98 (2H, t), 7.76 (2H, t), 7.56 1H, 1 1.3 Gy), 7.28-7.22 (1H, t), 7, 04 (IN, d, 2: 7.8 En), 6.90 (IN, 84, 1-9 Hp, 1-1.3 Hn), 6.80 (IN, 2.6 Hz), 6.66 (IN, give, 2-9 and 2.6 Hyyu), 6.46 (1H, 8), 4.53 (2H, 5), 2.88 (ZH, a, 32 5.1 Hz), 1, 31 (ZN, 5). 7.3.558 Ш24(33,4-ethylenedioxyphenyl)-5-fluoro-МА4- Similar to the preparation of М4-(ethylenedioxyphenyl)-5-fluoro-М2-|3-0М-

H2-(M-methylamino)carbonylbenzofuran-)methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(3,4-3-yl|-2,8-pyrimidinediamine (K926491) ethylenedioxyphenyl)-5-fluoro-MA- 12-(M-methylamino)carbonylbenzofuran-5-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction M2-(3,4-ethylenedioxyphenyl)-M4-(2-methoxycarbonylbenzofuran-5-1l)-5-fluoro-2 ,2-pyrimidinediamine and methylamine hydrochloride. IN NMR (SOZOYUIO 8105, 18), 7.944, 18, 1-5 Go), 7.59 (z, 70 2NU 7.44 (5, IN), 6.96 (0, 1Н, 1-- 2.4 Go), 6.82 (4, 1H, 2-8.4 Hz), 6.76 (46, 1H, 12 3.6 and 8.1 Gy), 4.22 (5, 2H), 4.21 (5, 2H), 2.95 (in, ZN); LC/MS: retention time: 17.76 min; purity: 9795; MS (m/z): 436 (MN). 7.3.559 M2-43, 5-dimethoxyphenyl)-M4-134(M- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-13-(M-methylamino)carbonylmethyleneoxyphenyl)- | methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine, IM2-(3,5-5-fluoro-2,4-pyrimidinediamine (KU26810) limethoxyphenyl)-M4-13-(M-methylamino)carbonylmethyleneoxyphenyl)-5-fluoro-2 ,4-pyrimidinediamine is obtained as a result of the reaction of M2-(3,5-dimethoxyphenyl)-MA-(3-ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine and methylamine hydrochloride. 1H NMR (COSO): 7.93 (4, IN, 1-3.9 Hz), 7.72 (5, IN, 7 1.8 Gp), 7.27-7.19 Um, 2H), 6.88 (a, 2H, 3- 2.4 Hz), 6.72 (t, 1H), 6.01 (1, 72.4 Gy), 4.54 (5, 2H), 3.67 ( 5, 6H), 2.89 (in, ЗН). 7.3.560 5-bromo-M2-3,4-ethylenedioxyphenyl)- Similar to the preparation of M4-(3,4-ethylenedioxyphenia)-5-fluoro-M2-|3-(M-m4-44(M-methylchlamino)carbonylmethyleneoxyphenyl| -2,4-pyrimidinediamivu, 5-bromo-M2-(3,4-methylamino)carbonylmethyleneoxyphenyl)- | ethylenedioxyphenyl)-Ma-I4-(M-methylamino)carbonylmethyleneoxyphenyl-2,4- 2,4-pyrimidinediamine (K925851) pyrimidinediamine is obtained as a result of the reaction of 5-bromo-M2-(3,4- ethylenedioxyphenyl)-MA-(4- methoxycarbonylmethyleneoxyphenyl)-2.4-pyrimidinediamine and methylamine hydrochloride. IN NMR (CO3OB): 7 8.01 (5, 18), 7.285:a, 29.3: 8.7 Hz), 7.09 (4, IN, 12 3.0 Hz), 7.08 (0 , 2H, 12 8.7 Gy), 6.814, 18, 1-58.7 Gy), 6.64(4, 1H, 1-87 Hm), 4.52 (5, 2H), 4.20 (05, NO ), 2.83 (5, ZNU; LC/MS: retention time: 19.13 min; purity: 9495; MS (m/z): 487 (MN). 7.3.561 12-(3-hydroxyphenyl)-5 -trifluoromethyl- Analogously to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-IM2-(13-(М-4-13-(М-methylamino)carbonylmethyleneoxyphenylI-2,4-pyrimidinediamine, M2 (3-4 and . methylamino)carbonylmethyleneoxyphenyl" | hydroxyphenyl)-5-trifluoromethyl-М4-Й3-(М methylamino)carbonylmethyleneoxyphenyl|- (5) 2,4-pyrimidinediamine (8926741) 2,4-pyrimidinediamine is obtained as a result of the reaction M2-(3-tihydroxyphenyl )-5- trifluoromethyl-M4-(3-M-methoxycarbonylmethyleneoxyphenyl)-2,4-lirnmidineliamine and methylamine hydrochloride. LC/MS: retention time: 18.52 min; purity: 9695; MS (m/zu: 434 (MN ). 7.3.562 М2,Ма4-bis4-(М-п- Analogously to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-im2-13-(М-(Че) butylamino)carbonylmethyleneoxyphene ill). methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine, 12, Ma-bis|a- (Mp. 5-piano-2,4-pyrimidinediamine (2925860) | butylamino)carbonylmethyleneoxyphenyl-5-cnano-2,4-pyrimidinediamine is obtained in Gee! as a result of the reaction of M2,M4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamine and p-butylamine. 1H NMR (PM5O-d6X GP 9.77 (B5, NU, 9.38 (b5, 1H), 8.42 (5, 1H), 8.09 (5, IN, I 5.4 Go), 8, 02 (6 1H, 1: 5.7 Hz), 7.48-7.34 (t, 48), che 6.93 (4, 2H, 1: 9.3 Hz), 6.82-6.72 (tt, 2NU, 4.47 (v, 2), 4.38 (5, 2H), 3.14-3.06 (t, 4H), 1.42-1.33 (t, 4H), 1 ... ): 546 (MN).

З5 7.3.563 M2,ma-bisrich (M- Analogously to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-|3-(M-(ee) isopropylamino)carbonylmethylethoxyphen | methylamino)carbonylmethyleneoxyphenyl/|-2 ,4-pyrimidinediamine, M2,MA-bistA-(M-yl)-5-cyano-2,4-pyrimidinediamine isopropylamino)carbonylmethidenoxyphenyl|-5-cyano-2,4-pyrimidinediamine (8925861) is obtained as a result of the reaction M2,M4 -bis(4-ethoxycarbonylmethyleneoxyphenyl)-2-cyano-2,4-pyrmidinediamine and isopropylamine. 1 H NMR (PM50-46):) 8.41 (5, 1H), 7.90(4.1H, 21-75 tsu 7.81 (0, EN, 37- 7.5 Hu, 7.50- 7.36 (t, 4H), 6.93 (d, 2H, 1- « 8.7 Go), 6.88-6.75 (t, 2H), 4.45 (v, 2H), 4.36 (5, 2H), 3.99-3.87 (t, 2H), 1.08 (4, 6H,

I- 3.0 Gy), 1.06 (4, NM, 1: 2.4 Gy); LC/MS: retention time: 23.45 min; purity: 8995; MS (m/z): 518 (MN). - c 7.3.564 MO, ma-bisi4-( Mep Analogously to the preparation of 144-(3,4-styrenedioxyphenyl)-5-fluoro-M2-Y13-0M-propylamino)carbonylmethyleneoxyphenyl) | methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M2,M4-bisy4-0M-p- and z»-5-cyano-2,4-pyrimidinediamine (2925853) | propylamino)carbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamine is obtained as a result of the reaction of M2,M4-bis(4-stoxycarbonylmethyleneoxyphenyl-5-cyano-2,4-pyrimidinediamine and p-propylamine. 1 H NMR (0М50О-46 ):71 9.78 (Be, 1H), 9.38 (5,

IN), 8.41 (5, 1H), 8.07 (a6, 2H, Z) 6.0 apa 22.5 Gy), 7.48-7.36 (t, 4H), 6.93, 2H, 128.7 Hz), 6.78 (4, ZN, 12 V, Hz), 4.48 (5, 2H), 4.39 (5, 2H.), 3.07 29, 4H, 12

Go! 72 Ha in 1.47-1.38 ( t, 4Н ), 0.90-0.77 ( t, 6Н У; РХ/MS: retention time: 23.67 min.; purity: 94 95; MS ( n /e): 519 (MH).

Go) 7-3.565 M2, Ma bisra-(M- Analogously to the preparation of M44(3,4-ethylenedioxyphenyl)-5-fluoro-M2-13-40M-morpholino)carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M2,M4-bisy 44(M-5-cyvno-2,4-pyrimidinediamine (K925854) | morpholino)carbonylmethyleneoxyphenyl|-5-cyano-2,4-pyrimidinediamine is obtained in -- as a result of the reaction of M2,M4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-(Ce) (42) with 60 b5 pyrimidinediamine and morpholine. IN NMR (Hum 50-46): GI 9.78 (B5, IN), 9.31 (Bv,

IN), 8.41 (5, IN), 7.43 (4, 4H, 18.1 Gy), 6.89 (4, 2H, 7-93 Hz), 6.75 (4, 2H, 1- 8.4

Hz), 4.84 (5, 2H), 4.74 (5, 2H), 3.76 and, 4H, 1-51 R ts), 3.62-3.50 (t, 4H), 3, 49-3.38 (t, 4H), 3.08-3.01 (t, 4H); PH/MS: retention time: 19.25 min.; purity: 89 50;

MS (m/hu: 574M NEU). 7.3.566 M2, MA-bisi44M. Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-Mm2-1341h-piperidino)carbonylmethyleneoxyphenyl|- / methylamino)carbonylmethyleneoxyphenyl)-2.4-pyrimidinediamine, M2,M4-bisy4-(M-5-cnano-2, 4-pyrimidinediamine (К925855) | piperidico)carbonylmethyleneoxyphene li-5-cyano-2,4-pyrimidineliamine is obtained as a result of the reaction of М2,М4-bis(4-ethoxycarbopylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamine and piperidine, 1Н АМ (apeton-db6): C 8.86 (B5, IN), 8.48 (b5,

IN), 8.34 (5, 18), 7.61-7.50 (t, 4H), 6.98 "y, 2H, 1-2 8.7 Gy), 6.90 (4, 2H, 12: 953 tsu 4.84 (5, 2H), 4.75 (v, 2H), 3.59-3.48 (t, 8H), 1.68-1.44 (t, 12H); LC/MS: duration of 70 retention: 24.76 min.; purity: 98 55; MS (m/z): 571 (MAX). 7.3.567 M2,ma-bisi44M- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5- fluoro-х2-(34(M-cyclopropylmethylamino)carbonylmethyl|methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2,M4-б1с/4-(M- enoxyphenyl|-5-cyano-2,4- peiclopropylmethylamino)carbonylmethyleneoxyphenip) -5-cyano-2,4-pyrimidinediamine pyrimidinediamine (K925859) is obtained as a result of the reaction of M2,IM4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamine and cyclopropylmethylamine. IN NMR (0M5O-y6): 9.78 (b5, 1H), 9.36 (5, 1H), 8.41 (5.18), 8.18 (5 1H, 2-2 5.1 Hz) , 8.19 (B 1H, 25 5.1

Gi), 7.52-7.38 (t, 4H). 6.94 (4, 2H, 1-8.7 Hz), 6.84-6.76 (t, 2H), 4.48 (v, 2H), 4.40 (v, 2NI), 3.00 (4, 4H, 2- 6.3 Hz), 0.97-0.88 (t, ?H), 0.40-0.33 (t, 4), 0.18-0.03 (t, 4H)U; 19E NMR (SOSIS): LC/MS: retention time: 24.58 min.; purity: 100 90,

MS (m/z): 543 (МН. 7.3.568 М4-(3-aminophenyl)-М2-(1,4-benzoxazine- | MA4(3-nitrophenyl)- М2-Ц2Н) 4-benzoxazine-3(4Н )-mono-6-yl|-5-fluoro-2,4-b-yl)-5-fluoro-2,4-pyrimidinediamine pyrimidinediamine (940 mg, 2.5 mmol) and ROS 1092 (300 mg, water content 5095) (K950254) are suspended in EYN (7 ml) and 1995 aqueous solution of NS (5 ml) and hydrogenated in a Parr reactor for 3 hours (22 oC, 4 atm). The suspension is filtered through celite and neutralized by adding K2SOZ. Solvents are removed, the resulting black sludge is suspended in MeOH. After adding silica gel (4 g), the volatile substance is removed under reduced pressure. The precipitate was subjected to column chromatography and chromatography on silica gel (SNCI3-acetone, 2:1), obtaining 186 mg of M4-(3-aminophenyl)-M24(1,4-benzoxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine in the form of a brown solid. IN NMR (OM 5О0-й6); 6 8.92 (5, 1H), 8.64 (5, 1H), 7.95 (a, 1H, 13.6 0), 7.1 (5, 1NU, 6.854-6.95 (t, Z ), 6.65 (49, 1H, 1-24, se 9.0 Gy), 6.46 (4, 1H, 7-8.1 Gy), 6.28 (d, IN, 3-81 Hz) , 5.62 (5, EN), 4.98 (5, 2H), 4.03 (t, 2H), 3.31 (t, 2); purity by LC/MS: 98.45; MS (m /z): 3527 (MA, 100). Ge) 7.3.559 144-(3,4-ethylenedioxyphenyl)-5-fluoro-ych2- M2-(3-Ethoxycarbonylmethyleneaminophenyl)-Mma4-(3,4-styrenedioxyphenyl)- 5-fluoro-2,4- (3-(M-2-pyrimidinediamine (50 mg, 9.11 mmol)) is dissolved in EYN:4-(2- morpholinoethyleneaminozharbonylmethyle | aminoethyl)morpholine (0.5 ml : 0.5 ml ), and the mixture is heated in a flask with a refluxing naminophenyl-2,4-pyrimidinediamine refrigerator for 3 hours (at an oil bath temperature of 100 0C). The mixture (Ce) (K950200) is cooled to 22 0C, dissolved in water and washed with EOAc, the organic phase is dried nal Me5O4, evaporate under reduced pressure, the precipitate is subjected to column chromatography on silica gel (SNCIZ:acetovn, 2: I) with the formation of M4-(3,4. (22) ethylenedioxyphenyl)-5-fluoro-M2-|3-04-2 - morpholinoethyleneamino)kar bonylmethyleneamicophenyl|-2,4-pyrimilindiamine. 1N or

NMR (0M850-abSOZOrU: 6 7.92, 1H, 1-1 Gy), 731 (4.1 H, 2-23 Hz), 7.20 (49, IN, 3- 2.7, 8.68 G i), 6.87-6.99 (t, 2H), 6.74 (b, IN, 1-8.8H i), 6.09 (t, IN), 4.19 s (t, 411) , 3.38 (t, 45), 3.16 (, 2H, 72 6.3 Hz), 2.78 J, 2H, 1- 6.3 Hz); cleanliness by

VH/MS: 99.20; MS (m/z); 524.01 (M, 100). so 7.3.570 ma-(3,4-ethylenedioxyphenyl)-M2-13-M- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-13-0M-methylamino)carbonylmethyleneaminophenyl | morpholinoethyleneamino)carbonylmethyleneaminophenyl|-2,4-pyrimidinediamine, M4-1-5-fluoro-2,4-pyrimidinediamine (K950191) | (3,4-ethylenedioxyphenyl)-M2-134(M-methylamino)carbonylmethyleneaminophenyl-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction 42-(3-ethoxycarbonylmethyleneaminophenyl)-M4-(3,4-ethylenedioxyphenyl)-5 -fluoro-2,4- « pyrimidinediamine and methylamine. LC/MS: duration of immersion: 17.32 min.; 20 purity: 99.395; MS (m/z); 425.04 (MN). - about 7.35 M2-(3-(M- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(340M- with amino)carbonylmethyleneaminophenyl|-M4- | morpholicoethyleneamino)carboniapmethyleneaminophenia)-2,4- pyrimidinediamine, M2-(3-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-(M-amino)carbonylmethyleneaminophenyl|-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4- in ! » pyrimidinediamine (K95019723 pyrimidinediamine is obtained as a result of the reaction of M2-(3- "ethoxycarbonylmethyleneaminophenyl)-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine and an aqueous solution of ammonia. LC/MS: retention time: 16.59 min.; purity: 98.895; MS (m/z): 411.02 (MN). 7.3.572 M443,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similar to the preparation of 44-(3,4- ethylenedioxyphenyl)-5-fluoro-M2-(3-(0M- (ee) I3-(m- morpholinoacetylenamino)carbonyl|-2,4-pyrimidinediamine, M4- morpholino)carbonylmethyleneaminophenyl)| | (3,4-styrenedioxyphenyl)- 5-fluoro-M2-Y3-04-ke-2,4-pyrimidinediamine (К950193) morpholino)carbonylmethyleneaminophenyl|-2,4-pyrimidinediamine is obtained as a result of re shares M2-(3-stoxycarbonylmethyleneaminophenyl)- M4-(3,4- ethylenedioxyphenyl). of 5-fluoro-2,4-pyrimidinediamine with morpholine. RH/MS: - retention time: 18.70 min.; purity: 85,890; MS (m/z): 481.05 (MN). "se 20 ma-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(3,4-ethylenedioxyphenia)-5-fluoro-Mm2-13-(0M» (42) ko 60 b5

I3-OM-(M-methyl)-morpholinoethyleneamino)carbonylmethyleneaminophenyl|-2,4-pyrimidinediamine, M4- piperazino)carbonylmethyleneaminophenyl | (3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-04-(M-methyl)piperazino)carbonyl 1,42,4-pyrimidinedismine (K950194) methyleneaminophenyl|-2,4-pyrimidinediamine is obtained as a result of reaction Ch2 -(3-ethoxycarbonylmethyleneaminophenyl)-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine and M-methylpiperazine. LC/MS: retention time: 15.75 min.; purity: 99.195; MS (m/z): 494.06 (MN). 7.3.574 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- Analogous to the preparation of 144-(3,4-styrenedioxyphenyl)-5-fluoro-M2-13-0M-

I3-0m-2- morpholinostipenamino)carbonylmethyleneaminophenyl|-2,4-pyrimidivdiamine, MA. hydroxyethyleneamino)carbonylmethylenezm | (3,4-ethylenedioxyphenyl)-5-fluoro-M2-|340M-2-inophenyl|-5-fluoro-2,4-pyrimidinediamine tihydroxyethyleneamino)carbonylmethyleneaminophenyl|-5-fluoro-2,4-pyrimidinediamine (K950195) is obtained in as a result of the reaction of M2-(3-stoxycarbonylmethyleneaminophenyl)-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine with 2-aminoethanol. LC/MS: retention time: 16.23 min.; purity: 97.3; MS (m/z): 455.02 (MN). 7.3.575 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Analogous to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(34(M- is-(M- morpholinoethyleneamino)carbonylmethyleneaminophenyl-2,4-pyrimidinediamine, M4- methylamino)styreneaminocarbonylmethyl | (3,4-ethylenedioxyphenyl )-5-fluoro-1х2-|3-(M-methylamino)styreneaminocarbonyl naminophenyl|-2,4-pyrimidinediamine methyleneaminophenyl-2,4-pyrimidinediamine is obtained as a result of the reaction M2-(3- (K950196) ethoxycarbopylmethyleneaminophenyl)-M4-( 3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine with M-methyl-ethylene-1,2-diamine. LCMS: retention time: 15.34 min.; purity: 98.25; MS (m/ z): 468.06 (МН). 7.3.576 M4-4(3,4-ethylenelioxyphenyl)-5-fluoro-M2- Analogous to the preparation of IM4-(3,4-styrenedioxyphenyl)-5-fluoro-Mm 2513- 40

I3-(M-morpholinostylenamino)carbonylmethyleneaminophenyl|-2,4-pyrimidineliamine, Ma» piperazino)carbonylmethyleneaminophenyl | (3,4-ethylenedioxyphenyl)-5-fluoro-M2-13-(04-1-5-fluoro-2,4-pyrimidinediamine (KU50197) | piperazino)carbonylmethyleneaminophenyl|-5-fluoro-2,4-pyrimidinedismine is obtained in as a result of the reaction of M2-(3-ethoxycarbonylmethyleneaminophenyl)-Ma-(3,4- ethidenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine with piperazine, LC/MS: retention time: 15.38 min.; purity: 93.25; MS (m/z): 479.99 (ME). M2 -|3- enaminophenia|-М4-(3,4- (M-benzylamino)styreneaminocarbonylmethyleneaminophenyl|-М4-(3,4- ethylenedioxyphenyl)-5-fluoro-2,4- ethylenedioxyphenyl)-5-fluoro-2,4 -pyrimidinediamine is obtained as a result of the reaction of pyrimidinediamine (K959198) M2-(3-ethoxycarbonylmethyleneaminophenyl)-M4-(3,4 ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine and M-benzyl-ethylene-1,2-diamine. /MS: retention time: se 17.70 min, purity: 92.599, MS (m/z): 544.04 (MN).

М2434М М -bis(2-М- Analogous to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-Г13-(0М- He) hydroxyethyl)amino)carbonylmethylene | morpholinoethyleneamino)carbonylmethyleneaminophenyl|-2,4-pyrimidinediamine, M2-Y3- nophenyl|-Ma4-(3,4-ethylenedioxyphenyl)-3- | (M,M'-bis(2-M-hydroxystyl)amino)carbonylmethyleneaminophenyl|-M4-(3,4-fluoro-2,4-pyrimidinediamine (K950199) ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained in as a result of the reaction

M2-(3-ethoxycarbonylmethyleneamicophenyl)-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-(Che)pyrimidinediamine with M.M"-bis(2-hydroxyethylene)amine. LC/MS: retention time : 15.81 min; purity: 99495; MS (m/z): 499.01 (MNE). He) 7.3.579 5-"fluoro-Ma-(3-hydroxyphenyl)-M2-(3-(M- Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fcor-M2-|3-(M» methylamino)carbonylmethyleneaminophenyl|morpholinostylenamino)carbonylmethylevaminophenyl|-2,4-pyrimidinediamine, 5-che ».a-pyrimidinediamine (KU50217) fluoro-M4-(3-hydroxyphenyl)-42-|3-(M-methylamino)carbonylmethyleneaminophenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction M2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-M4-(3-hydroxyphenyl )-2,4-s pyrimidinediamine with methylamine LC/MS: retention time: 14.41 min;

ZB purity: 93.05; MS (m/z): 383.02 (MNK). (ee) 7.3.580 M243- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-YM2-(3-(M-aminocarbonylmethyleneaminophenyl)-5-morpholinoethyleneamino)carbonylmethyleneaminophenylI-2,4-pyrimidinediamine, M2-( 3-fluoro-M4-(3-hydroxyphenyl)-2,4-aminocarbonylmethyleneaminophenyl)-5-fluoro-МА43-hydroxyphenyl)-2,4-pyrkimidinediamine (K950219) pyrimidinediamine is obtained as a result of the reaction I42-(3-ethoxycarbonylmethyleneaminophenyl)-5 -fluoro-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine with an aqueous solution of ammonia. LC/MS: retention time: 14.23 min; purity: 95.09; MS (m/z): 369.03 (MN). 2 7.3.581 1h2-I3-(M,M- Similar to the preparation of IM4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-(M- with dimethylamino)carbonylmethyleneaminophen | morpholinostylenamino)carbonylmethyleneaminophenyl|-2,4 -pyrimidinediamine, IM2-|3-chyl|-5-fluoro-M4-(3-hydroxyphenyl)-2,4- (M.M-dimethylamino)carbonylmethyleneaminophenyl|-5-fluoro-M4-(3-hydroxyphenyl)- 2,4» and - pyrimidinediamine (K9502720) pyrimidinediamine is obtained as a result of the reaction of 42-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-M4-4(3-hydroxyphenyl)-2,4-pyrimidinediamine with dimethylamine. PH/MS: retention time: 16.59 min; purity: 96.50; MS (m/zu: 397.06 (MNE). 7.3.582 5-for-MA-(3-hydroxyphenyl)-M2-13-(M- Analogous to the preparation of M4-(3,4-ethylenepioxyphenyl)-5-fluoro -M2-13-(M- (ee) morpholino)carbonylmethyleneaminophenyl| | morpholinosyleneaminocarbonylmethyleneaminophenyl|-2,4-pyrimidinediamine, 5- -2,4-pyrimidinediamine (KU50221) fluoro-M4-(3-hydroxyphenyl)-Ich2-1344M- morpholino)carbonylmethyleneaminophenyl |-2,4-

Kkz pyrimidinediamine is obtained as a result of the reaction of M2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine with morpholine. LC/MS: duration of incubation: 16.29 min; purity: 91.55; MO (m/z); 439.03 (MN). "o 20 5-fluoro-M4-(3-hydroxyphenial)-M2-|3-(M- Analogous to the preparation of 1Ch4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-13-0M- 42) ko 60 b5 piperazino)carbonylmethypenaminophenyl. | morpholinostylenamino)carbonylmethyleneaminophenyl|-2,4-pyrimidinediamine, 5-1-2,4-pyrimidinediamine (KO50222) fluoro-ma-(3-hydroxyphenyl)- M2-(3-(Mi-piperazino)carbonylmethyleneaminophenyl)|-2,4 - pyrimidinediamine is obtained as a result of the reaction of M2-(3" ethoxycarbovylmethyleneaminopheni)-5-fluoro-M4-(3-hydroxypheniyl)-2,4-pyrimidinediamine and piperazine. LC/MS: retention time: 13.04 min; purity: 89.95; MS (m/z)y: 438.06 (MN). 7.3.584 5-fluoro-Ма4-(3-hydroxyphevyl)-М2-/3-PM- Similar to the preparation of М4А-(3,4-ethylenedioxyphenial)-5-fluoro-М2-ІІ3-(0М- (M. morpholinoethyleneamino) carbonylmethyleneaminophenyl-2,4-pyrimidinediamine, 5-methyl)liperazino|carbonylmethyleneamine | fluoro-Ma-(3-hydroxyphenyl)-M2-I3-(M-(M-ophenyl-2,4-pyrimylinliamine (2950223) | methyl)piperazino|carbonylmethyleneaminophenyl-2,4-pyrimidinediamine is obtained as a result of the reaction of M2-(3Z -ethoxycarbonylmethyleneaminophenyl)-5-fluoro-Ma4-(3-hydroxyphenyl)-2,4-pyrimidinediamine with M-methyllyperazine. LC/MS: 70 retention time: 12.06 min; purity: 98.79; MS (m/z ): 452.06 (MNK), 72.3.585 5-fluoro-M4-(3-hydroxyphenyl)-142-13-(0M- Similar to the preparation of M4-(3,4-ethylenedioxyphenip)-5-fluoro-M2-13 -(M- 2- morpholinoethyleneamino)carbonylmethyleneaminophenyl|-2,4-pyrimidinediamine, 5- hydroxyethylamino)carbonylmethyleneamine | fluoro-Ma-(3-hydroxyphenyl)-і4х2-13-15-2-ophenyl)-2,4-pyrimidinediamine ( 2950224) | hydroxyethylamino)carbonylmethypenaminophenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of M2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-Ma44(3-tihydroxyphenia)-2,4-pyrimidinediamine and 2-aminoethanol. LC/MS: retention time : 13.28 min.; purity: 97.39; MS (m/z): 413.04 (MN Yu). 7.3.586 5-fluoro-M4-(3-hydroxyphenyl)-M2-13-((M- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-(M-methylamino) stylaminoicarbonylmethylene | morpholinostylenamino) carbonylmethyleneaminophenyl|-2,4-pyrimidinediamine, 5- gminophenyl|-2,4-pyrimidinediamine fluoro-M4-(3-hydroxyphenyl)-M2-13-((M- (К950225) methylamino)ethylamino)carbonylmethyleneaminophenyl| -2,4-pyrimidinediamine is obtained as a result of the reaction of M2-(3-ethoxycarbonylmethyleneaminophenyl)-5-fluoro-(3-tihydroxyphenyl)-2,4-pyrimidinediamine with M-methyl-ethylene-1,2-diamine.

PH/MS: retention time: 12.31 min; purity: 94.7 MS (m/z) and: 426.01 (MN). 7.3.587 5-fluoro-M4-(3-hydroxyphenyl)-ShM2-13-I0M- | Similarly to the preparation of ИМ4-(3,4-ethylenedioxyphenyl)-3-fluoro-М2-И3-04-72. morpholinoethyleneamino)carbonylmethyleneaminophenyl|-2,4-pyrimidinediamine, 5-morpholinosylamino)carbonylmethylene | fluoro-Mm4-(3-hydroxyphenia)-M2-(3-(0M-2» minophenyl|-2,4-pyrimidinediamine morpholinoethylamino)carbonylmethyleneaminophenyl)-2,4-pyrimidinediamine (8950226) is obtained as a result of the reaction of M2-(3- ethoxycarbonylmethyleneaminophenyl)-5-fluoro-

Ma-(3-hydroxyphenyl)-2,4-pyrimidinediamine with M-morpholinylethylamine, LC/MS: retention time: 12.66 min.; MS (m/z): 482.39 (MN Kk). Ha 8935184: 5-fluoro-MO2-14-(M- Analogous to the preparation of M4-(3 4-styrenedioxypheny)-5-fluoro-M2-(340M- o methylamino)carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenyl)-2,4- pyrimidinediamine, 5-dugor-M2-(440M-

M443.4 propylenedioxyphenyl)»-2,4» methylamino)carbonylmethyleneoxyphenyl|-M4-(3,4-propylenedioxyphenyl)-2,4- pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M2-|4- (methoxycarbonylmethyleneoxy)phenyl| -Ma-3,4-propylenedioxyphenia)-2,4-pyrimidinediamine with МЕ2МН.НСЙ and 1-Рг2 МЕ: in methanol. LC/MS: duration (Ce) of retention: 6.91 min.; purity: 9895; MS (m/z): 440 (MN). 7.3.589 KO35196: M2-1341-bis0h- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-(M-(e») methylaminocarbonyl)stoxy)phengl|-5- methylamino) carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M2-/3-(1-bisM-fluoro-M4-(4-isopropoxyphenia)-2,4-methylaminocarbonyl)ethoxy)phenyl)-5-fluoro-M4-(4-isopropoxyphenyl)-2 ,4-pyrimidinamine pyrimidikamine is obtained as a result of the reaction of M4-|3-41- ach bis(ethyloxycarbonyl)ethoxy)phenyl-3-fluoro-M2-14-isopropoxyphenyl)-2,4-pyrimidinediamine with Me2H.HCY and i-PhoMEx in the presence of methanol. IN NMR se (OM5O-4b): PO 9.18 (5, 1H), 9.15 (5, 1H), 8.07 (arr ai, 2H, 1- 4.7 Hyv), 8.01 (4 , 1H, /e 3.5 Hz), 7.65-7.62 (t 2H1), 7.36 (Be 5, NN), 7.28 (44, 1H, 121.1 i 8.2 Hz) , 7.03 (B 1H, so /- 8.2 Gy), 6.87 (4, ZA, 7: 8.8 Gy), 6.35 (ad, 1H, 7 1.1 m 8.8 Gy ), 4.54 (4, IN, 1-6

Gy), 2.62 (a, 6H, 12 4.7 Gy), 1.49 (5, ЗН), 1.23 (4, 6H, 1- 5.8 Gy). PH/MS: duration of retention: 19.40 min.; purity: 94; MS (m/z3u: 497 (MN). 7.3.590 KOU35202: 5-fluoro-M2-13-0M- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-(0M- methylamino)carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenyl)-2,4-lyrimidinediamine, 5-fluoro-M2-13-0х-

Ma-(3 4"propylenedioxyphenyl-2,4-methylamino)carbonylmethyleneoxyphenyl-M4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M2-(3- (methoxycarbonylmethyleneoxy)phenyl| -M4-(3,4-propylenedioxyphenyl)-2,4- with pyrimidinediamine with ME2MN.HCl. TN NMR (0M50-a6): 1) 9.21 (5, 1H, 9.19 (5.1), 8.064, 1H, 12 4.1 Gy), 7.94 (d, IN, 72 3.5 Hz), 7.42-7.38 (t, 2), 7.30 (db, 2H, 1-7 ,6 h Hz), 7.12 (0, 1H, 15: 7.6 Hz), 6.89 (y, 1, 72: 8.2 Hz), 6.47 (I, 1H,1- 2, 3 and 8.8 Gy), and t 4.33 (5, 2H), 4.11-4.03 (t, 4H), 2.63 (4, ZN, 1-4.7 Gy)), 2 ,08-2,03 (t, 2H). PH/MS: retention time: 17.33 min.; purity: 9896; MS (m/z): 440 (MN). 73591 K935206: M2,M4-bis 1-04- Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-(M-methylplaminocarbonyl)methyl-indazolin-b- | methylamino)carboniamethyleneoxyphenyl-2 ,4-pyrimidinediamine, M2, Ma-bis|1-0ch-yl|!-5-fluoro-2,4-pyrimidinediamine methylaminocarbonyl)methyl-indazolin-b-yl)-5-fluoro-2,4-pyrimidinediamine is obtained by as a result of the reaction of M2,MA-bisi and (methoxycarbonyl)methyl-indazolin-b-yl1-5-fluoro-2,A-pyrimidinediamine with Me2MH.HCl and KRIM: in the presence of methanol. IN NMR co (0M50-46): C 9.56 (5, 18), 9.40 (5, 1H), 8.17 (8, 1H, 1- 3.5 Gy), 8.12 (5, 1H), 7.99 (5, 1H), 7.96 (in, 2NU, 7.90 (5, 2NI), 7.66 (4, 1H, 1- 8.8 Hn), 7.564, 1H, 7 - 8.8 Gy), 7.49 - "a, 1Н.31-1.7 p 8.8 Hz), 7.34 (40, IN, 1- 1.7 and 8.8 Gy), 4, 90 (5, 2H), 4.66 (5, 21), 2.56 sho shi (a, vn, )- 4.11 Hm). LC/MS: retention time: 13.85 min.; purity: 9895; MS (Se) 42) ko 60 b5

02020512 1 1 21121 geo 7.3.,592 K935212: Ma-(3,4 ethylenedioxyphenyl)-3- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenia)-5-fluoro-M2-(34(0M-fluoro-M244114(M- methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3,4- methylaminocarbonyl)methyl -indazelin-b-|ethylenedioxyphenyl)-5-fluoro-х2-|140M-methylaminocarbonyl)methyl-indazolin-b-yl|-yl)|-2,4-pyrimidinediamine 2,4-pyrimidinediamine is obtained as a result of the reaction M4-( 3,4-ethylenelioxyphenyl)-5-fluoro-M2-(1-(methoxycarbonyl)methyl-indazolin-b-yl|-2,4-pyrimidinediamine and

MegMnN.NSI. TN YAM? (PM5O-06): 159.35 (5, IN), 917 (5. NN), 8.07 (4, 1Н, 12 4.8

Gy), 7.92 (5, IN), 7.89 (c, IN), 7.66 (a, IN, 2: 4.7 Gy), 7.54 (4, 1H, 72 8.8 Gy ), 7.35-7.24 (t, ZNU, 6.76 (8, 1H, ee 8.8 Hz), 4.77 (5, 2H), 4.20 (5, 4H), 2.57 (4 , ZN, 14.7

Gi). PH/MS: retention time: 15.82 min.; purity: 9495; MS (m/z): 450 (MN yayu). 7.-3.593 B935213: M4-(3,4-ethylenedioxyphenyl)-5- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-IM2-IZ4M-fluoro-M2-13-(2-(M-methylamino)carbonyl- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M44( 3,4-70 fur-4-yl)methyleneoxyphenyl|-2,4- styrenedioxyphenyl)-5-fluoro-M2-(3-(2-(M-methylamino)kaubonin-fur-4-pyrimidinediamine yl)methyleneoxyphenyl/) -2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-Mm2-(3-(2-methoxycarbonyl-fur-4-yl)methyleneoxyphenyl). 2,4-pyrimidinediamine with МЕ2МН .NOI and i-RG2ME 18 YAM (0M50-a6): H19.17 (5, 2H), 8.30 (d, IN, 7-- 4.7 Ha), 8.05 (0, 1H, 4- 35 Go), 7.42 (v, 1H), 7.29-7.19 (t, 2H), 7.096 IN, 158.2 Go), 7.02 (4, 1H, /- 2.9 Hn) . , 2H), 4.21-4.18 (t, 4H), 2.70 (b, ЗН, 1-4.7 Gy). LC/MS: retention time: 18.85 min.; purity: 9196; MS (m/z): 492 (pl. 7.3.594 K915216: 5-fluoro-M2-(44(M- Analogous to the preparation of IM4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-0M- methylamino)carbonylmethyleneoxyphenyl)-|methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-M2-14-(M-

Ma-(1-methyl-indazolin-5-yl)-2,4-methylamino)carbonylmethyleneoxy)phenyl-M4-(1-methyl-indazolin-5-yl)-2,4- pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of 5- fluoro-2-|4- (methoxycarbonylmethyleneoxy)phenyl |-M4-(I-methyl-indazolin-5-1l)-2,4-pyrimidinedigmine with Me2MH.HCI. 1H NMR (0M50-46X: P 9.31 (5, 1H), 9.00 (5, 18), 8.17 (5, IN), 8.02 (9, IN, /- 3.5 Hyd) . , - 8.8 Gah), 4.36 (5, 2H)U, 4.03 (8, ZNU, 2.63 (4, ZN, 3-47

Hz). PH/MS: retention time: 14.81 min.; purity: 9995; MS (m/zu: 422 (MN). 7.3.595 vo35217: M2,ma-bisi 1-0M- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-134(M-methylaminocarbonyl)methyl -indazolin-5-|methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamic, M2.M4-bis(1-(M-yl-5-fluoro-2,4-pyrimidinediamine methylaminocarbonyl)methyl-indazolin-5-yl|- 5-Fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M2,M4-bis|I -(methoxycarbonyl)methyl-indazolin-b-yl|-5-fluoro-sem 2,4-pyrimidinediamine with Me2MH.HCI. 1H NAM ? (0M50-46u: C 9.35 (5.1H), 9.15 (5.7 o

NU, 8.09-8.06 (t, 2H)), 7.97-7.96 (t, 2), 7.91 (5, NN), 7.70 (5, IN), 7.69 (5 , IN), 7.54-7.55 (t, 2), 7.48-7.40 (t, 2, 5.065, 2H)), 4.97 (5, 2H), 2.62 (0, ZY, 3-4,7

Giu, 2.61 (4, ZN, 1-4.7 Gy). LC/MS: retention time: 12.54 min; purity: 9595;

MS (m/z): 503 (MN). 7.3.596 114-4(3,4-ethylenedioxyphenyl)-5-fluoro-1M2- | M4-(3,4-ethylenedioxyphenyl)-5- (Che) 13-12-(M-cmorpholino)ethyleneoxy|phenyl|- is placed in a dry reactor with a rubber membrane. fluoro-M2-|3-(M-morpholino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine (0.019 2,4-pyrimidinediamine (KU26486) is, 0.04 mmol) and tetrahydrofuran (1 mL). Boronmetium-He sulfide complex (0.044 ml, 0.088 mmol) was added to this mixture, after which the mixture was stirred at room temperature for 2 hours. The boranemethyl-sulfide complex is evaporated, the reaction is quenched with MeOH (CAUTION: when MEOH is added, violent evolution of hydrogen gas occurs), then heated for 30 min. The solvent is removed, and the precipitate is resuspended in MeOH, then extracted with EIUAs; EUAs are evaporated, the precipitate is purified by the preparative method

TLC to give 74-(3,4-ethylenedioxyphenyl)-5-fluoro-m2-13-(2-(M- I c morpholino)styreneoxy |phenyl|-2,4-pyrimidinediamine. IN NMR (SOSISU: CI 8, 20 (8, 1), 8.01 (4, 1H, 42: 6 Gy), 7.26-7.05 (t, 3), 7.05-6.97 (t, ZN), 6.82 (4 , 1H, 1:93

Ty), 6.67 (4d, 1H, 15 1.8 and 8.1 Gy), 4.44 (I, 2H), 4.27 (v, "H), 4.14 (t, 2H), 3.76 (t, 2H), 3.29 (6 2H, 225 5.4 Hyd), 3.05 (t, 280), 2.88 (t, 2H). 7.3.597 443,4-Stylenedioxyphenyl)-5-fluoro-MO- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-E3-(24(M. « (2(M-morpholinomethylene)benzofuran-5- | morpholino)ethyleneoxy|phenyl-2,4--pyrimidinediamine . M4-(3,4-ethylenedioxyphenyl)-5-fluoro-m2-12-(M.-c morpholino)carbonylbenzofuran-5-yl1-2,4-pyrimidinediamine and boranemethyl-sulfide complex. 1H NMR (SOZOI 8.65 (0, 2Н, 5-21 Hm), 8.30 (40, 7Н, p 1-21 and 9.6 и), 7.73 (d, 7Н, 1-9, Ж3 Hz), 7.49 ( B5, 2H), 7.32 (t, 1H), 5.74 (pu, other), and » 4.24 (5, 4H), 3.97 (8, 2H), 3.78 (t, 4H ), 3.56 (t, 4H). 7.3.598 MaА43,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-13-(12 -(M- (3-D-(M-methylamino)ethyleneoxyphenyl|- | morpholino)stylenoxy Iphenyl|-2,4-pyrimidivdiamine, M4-(3,4-ethylenedioxyphenyl)- 2,4-pyrimidinediamine (K926510) 5- fluoro-M2-(3-(2-(M-methylamino)stylenoxy|phenyl|-2,4-pyrimidonediami N

Go! are obtained as a result of the reaction of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|340M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine and boranemethyl sulfide complex. IN NMR (COSO): 8.00 (a, IN, 7- 5.2 Gy), 7.50-7.30 (t, ko 2), 7.16-6.80 (t, 5H), 4.28 (t, 1H), 4.27 (88, 4H), 4.22 (t, 1H), 3.44 (t, 2H)), 2.79 (4, ЗН, 2-3Gy); LC/MS: retention time: 15.64 min; purity: 9605; MS (m/z): -th AT2 (MNU. (Se) 42) ko 60 b5

7.3.599 5-fluoro-M4-(3-hydroxyphenyl)-M2-E2-(M- Analogous to the preparation of IM4-(3,4-ethypendioxyphenyl)-5-fluoro-M2-|3-I2-4(M- piperazinomethylene )benzofuran-5-yl-morpholino)styreneoxy|phenylp|-2,4-pyrimidinediamine, 5-fluoro-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (K926770) M2-(2(M-piperazinomethylene)benzofuran -z-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-IM4-(3-hydroxyphenyl)-12-12404- piperazino)carbonylbenzofuran-5-ylI-2,4-pyrimidinediamine and boranemethyl sulfide complex. LC/MS: retention time: 12.06 min; purity: 7595;

MS (m/z): 435 (MN). 7.3.600 M4-4(3,5-dimethyl-4-hydroxyphenyl)-5- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-(24(M- fluoro-M2- 13-12-(M-morpholino)stylenoxyphenyl/|-2,4-pyrimidinediamine, M4-443,5-dimethyl-4-morpholino)stylenoxy |phenyl|-2,4-hydroxyphenyl)-5-fluoro-M2- 13-(2-(M-morpholino)stylenoxy |phenyl|-2,4-pyrimidinediamine (KO40255) pyrimidinediamine is obtained as a result of the reaction M4-(1,5-pimethyl-4-hydroxyphenyl)-5-fluoro-M2-I3- (M-morpholino)carbonylmethyleneoxyphenyl)-2,4-pyrimidineamine and. boranemethyl-sulfide complex. LC/MS: retention time: 15.94 min; purity: 9995; MS (m/z): 454 (MN); IN NMR (OM5O0-ybuK at 9.16 (18, 5), 9.07 (1H, 5), 8.15 (18, 5), 8.11 (1H, a, 7- 3.9 Hz), 7.40- 7.30 (4H, t), 7.13 (IN, b 8.1 Gy), 6.55 an, aa, 1-8.1 Gy, 3.2 Hz), 4.01 (2H, , 1 - 5.7 Gy), 3.65 (4H, 1, 15 4.2 Gy), 2.72 (2H,

In: 5.7 Hn), 2.515 (4H, 1, 12:45 Hz), 2.24 (6H, 5). 7.3.601 M4-(3,5-dimethyl-4-hydroxyphenyl)-3- Similar to the preparation of M4-43,4-ethylenedioxyphenia)-5-fluoro-M2-(3-(2-0M- fluoro-m2-(3 -(241h-morpholino)stylenoxy |phenyl|-2,4-pyrimidinediamine, M4-(3,5-limethyl-4-piperazino)stoxy|phenyl|-2,4- hydroxyphenyl)-5-fluoro-M2-|3 -(M-piperazino)carbonylmethyleneoxyphenyl|-2,4- pyrimidinediamine bis pyrimidinediamine is treated with a boranemethyl-sulfide complex with the formation of hydrochloride Kk 945142) M4-(3,5-dimethyl-4-hydroxyphenium)-5-fluoro-M2-13-( 2-(M-piperazino)ethyloxy|phenia|- 2,4-pyrimidinediamine, which is treated with 4M NOSI in total, in dioxane (3 ml) followed by crystallization with MEONLYO As with the formation of M4-(3,5-dimethyl-4-hydroxyphenia) )-5-fluoro-M2-(3-H2-(M-piperazino)ethoxy |phenyl|-2,4-pyrimidinediamine bis hydrochloride. 1 N NMR (SP3ZOI):6 2.17 (in, 6H), 3, 66 (t, 190, 4.26 (, 1-5 4.5

Gy, 2), 6.93 (44, 1-2 1.5, 7.7 Hz, IN), 7.10-7.13 (up, 2H), 7.17 (z, 28), 7, 31 0.1-84

Ha, 1H), 7.98 (9, 22 6.0 Sy, 18); 192 NMR (282M Hn, CO3OYU):6-162.93; VH/MS: retention time: 13.25 min; purity: 96.0895; MS (m/z) in: 453.09 (MN). 7.3.502 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-(2-04- (4-(2 -hydroxyethyloxy)phenyl|-2,4-morpholino)ethyleneoxy|phenyl|-2,4-pyrimidinediamine, M4-(3,4-ethylenedioxyphenyl)-5-pyrimidinediamine (KO45144) fluoro-m2-(4-(2- Tihydroxyethoxy)phenyl|-2.4-pyrimidinedismine is obtained as a result of the reaction of 1M2-(4-carboxymethyleneoxyphenyl)-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-se pyrimidinediamine with a boranemethyl-sulfide complex. 1H NMR (acetone -yb):0 3.86 (i, 1 4.8 Hz, 2H), 4.04 (1-2 4.8 Gy, 2H), 4.28 (t, 4H), 6.78 (8, 329.0 Hz, 18), Ge) - 5.86 (0, 3- 9.0 Gy, 2), 7.18 (40. 15: 2.7, 8.7 Gy, 18), 7.47 (8 , 12 2.7 Gu, 18), 7.63 in 1-9.0 Hz, 2H), 7.91 (4, 7- 3.6 Hp, 1), 8.29 (g, IN, MH) , 8.31 (B, IN, MN); 194 YAMA (282M Gu, acetone-d6):5-169.18; РХ/MS: retention time: 17.41 min; purity: 98.3695; MS (m/z): 399.01 (MN). "from 7.3. 603 Mm4-(3-chloro-4-hydroxy-5-methylphenyl)-5- | Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-(2-0M-fluoro-M2-13-(2-(M-morpholino|ethyleneoxyphenyl|-2,4-pyrimidinediamine), M4 -(3-chloro-4-thiproxy-5-He»! piperazino)ethoxy |phenyl-2,4- metkyphenyl)-5-fluoro-M2-|3-(M-piperazino)carbonylmethyleneoxyphenyl|-2,4- pyrimidinediamine pyrimidinediamine dihydrochloride is treated with a boranemethyl-sulfide complex, obtaining (K945150) M43-chloro-4-hydroxy-5-methylphenia)-5-fluoro-M2-|3-124(M- i piperazino)ethyloxyphenylI-2,4-pyrimidinediamine, which subsequently process 4M

NOI in dioxane (3 ml) followed by crystallization from MEONLEUACs with the formation of sem 144-(3-chloro-4-hydroxy-5-methylphenia)-5-fluoro-2-(3-12-04- piperazino)ethoxy|phenyl| -2,4-pyrimidinediamine bis hydrochloride. IN NMR c (С9ЗО0):6 2.21 (5, ЗН), 3.72 (t, ТОН), 4.35 (, 3- 4.5 Hz, 2Н)), 6.95 (y, 1- 1.5 and 9.0

Hz, 1, 7.11-7.14 (t, 2H), 7.26 (9, 7- 0.9 and 2.7 Hz, IN), 7.34 (0 1- 8.4 Hz, IN ), 7.50 (4.124 Gy, 1H), 8.03 (a, 15 5.4 Hz, IN); TUR NMR (282M Gy, SOZOBUO- 162.74; RH/MO: retention time; 14.50 min; purity: 94.7590, MS (m/z)y: 472.98 (MN). « 7.3.604 M4 -(3,5-dimethyl-4-methoxyphenyl)-5- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-12-(0М-

Ffluoro-M2-I3-12-(M-piperazino)ethoxy)morpholino)ethyleneoxy |phenyl)-2,4-pyrimidinediamine, M4-(3,5 dimethyl-4-b-phenyl)|-2,4-pyrimidinediamine methoxyphenyl)-5-fluoro-142-(3-(M-piperazino)carbonylmethyleneoxyphenyl|-2,4-s dihydrochloryl (8945157) pyrimidinediamine is treated with a boranemethyl-sulfide complex, obtaining

CHM4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-M2-I3-412-(M-piperazino)ethyloxypheny l|-h » 2,4-pyrimidinediamine, which is subsequently treated with 4M NH in dioxane ( 3 ml) with subsequent crystallization from MEON/LEOAc with the formation of M4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-M2-(3424(M-piperazino)stoxy|phenyl|-2,4-pyrimidinediamic bis hyprochloride. IN NMR (CO3OB):6 2.23 (5, 6NI), 3.66 (t, ION), 3.72 (8, ЗН), 2.1 (B 12: 4.5 Hz, 2Н )), 6.95 (48, 1-1.8 and 8.4 Go, 18), 7.09-7.15 (t, 28), 7.27 (5, 2H), 7.32 (, 1-8.1 Hu, 1H), 8.01 (a, 7: 5.4 Ha, 18); 197 YAM (282M Hn, pre-trial detention center: B-162.71; o RH/MS: retention time: 16.41 min; purity: 97.50995; MS (m/z): 467.12 (MN. de 7.3.605 Ma-(3,4-ethylenedioxyphenyl. 5-fluoro-M2- | As a result of the reaction of equal parts of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(2-(M- (24(M-piperazino) carbonylbenzofuran-piperazinecarbonylbenzofuran-5-ylI-2,4-pyrimidinediamine with hydrogen chloride (4M, - 5-yl)|-2,4-pyrimidinediamine hydrochloride | dioxane) in methanol at a temperature of 0 oC with subsequent dilution with dry (K926501) simple ethyl ether or ethyl acetate, a precipitate forms.

And fluoro-Mm2-12-(M-piperazino)carbonylbenzofuran-5-yl|-2,4-pyrimidinediamine (42)

F) ko 60 b5 tetrachloride. IN NMR (SRZOYIO 7.974, 1H,2- 5.4 g), 7.924, 1H, 2 18 g), 7628, 1H, 2 8.2 Ha), 7.48 (5, 1H), 7.43 (49 , 1H, 2-32 2.4 and 8.7 Hz), 7.17 (0, 1H, 1-2.4 Hn), 6.98 (46, 1H, 2- 2.4 and 8.7 Go ), 6.77 (a, IN, 1-8.7 Go), 4.13 (t, 43), 402 (8, AN), 3.38 (1, 4H, 75 5.7 Go); LC/MS: retention time: 15.12 min; purity: 8995; MS (m/z); 491 (MN). 7,3.606 M443 4-ethylenedioxyphenyl)-5-fluoro-M2- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-Ch2-12-04- (3-(M-piperazino)carbonylbenzofuran-5-yl |-2,4-pyrimidinediamine hydrochloride, M4-(3,4- piperazino)carbonylmethyleneoxyphenyl|- | ethmlenedioxyphenyl)-5-fluoro-M2-(3-(M-piperazino)carbonylmethyleneoxyphenyl|-2,4- 2.A- Pyrimidinedigmine hydrochloride pyrimidinediamine hydrochloride is obtained as a result of the reaction of M4-(3,4- (8926504) ethylenedioxyphenyl)-5-fluoro-M2-|3-(M-piperazino)carbovylmethyleneoxyphenyl|-2,4- pyrimidinediamine and hydrogen chloride. 1H NMR (0М5О0 -46:0 9.6 (B5, 1H), 9.04 (bv,

IN), 8.12 (4, IN, 72 3.6 Gy), 7.25-7.00 (t, 5H), 7.81 (4, 1H, 42: 8.7 Hz), 6.54 (y , IN, /- 8.4 Hp), 4.74 (5, 2H), 4.22. (5, 4), 3.54 (t, 4H), Z1 (pi, NU; RH/MS: retention time: 15.34 min; purity: 10095; MS (m/z): 481 (MNK. 7.3. 607 M4-(3,4-Stylenedioxyphenyl)-5-fluoro-Х2- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(2-(M- methylaminoethyl)phenyl|-2,4-piperazino)carbonylbenzofuran-5-yl|-2,4-pyrimidinediamine hydrochloride, M4-(3,4-pyrimidinediamine hydrochloride ethylenedioxyphenyl)-5-fluoro-M2-13-(2-4( M-methylamino)stiloxy |phenyl|-2,4- (8926509) pyrimidinediamine hydrochloride is obtained as a result of the reaction M4-(3,4- ethylenedioxyphenyl)-5-fluoro-M2-13-12-(M-methylamino)stiloxy|phenyl |-2,4-pyrimidinediamine with hydrogen chloride (4M, dioxane). LC/MS: retention time: 15.88 min; purity: 9295; MS (m/z): 412 (MH). 7.3.608 M443,4- ethylenedioxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-12-(M- (3-12-(M-morpholino)ethyloxy|phenyl)-2, 4-|piperazino)carbonylbenzofuran-5-1l)-2,4-pyrimidinediamine hydrochloride, YM4-(3,4-pyrimidinediamine hydrochloride ethylenedioxyphenyl)-5 -fluoro-M2-(3-12-(m-morpholino)styloxy Iphenyl|-2,4- (K926511) pyrimidinediamine hydrochloride is obtained as a result of the reaction IM4-(3,4- ethylenedioxyphenyl)-5-fluoro-M2-(3 -12-(M-morpholino)styloxy|phenyl)-2,4-pyrimidinediamine and hydrogen chloride. IN NMR (SOZOYUKO 7.98 (4, IN, 1- 5.4 Gy), 7.34 1H, 8.4 Gy), 7.16-6.81 (t, 5H), 4.42 (t, 1H), 4.40 (t, 2H), 4.25 (t, 5H), 8.10 (t, 2H), 3.90 (vv, 2H), 3.60 (t, 4H); PH/MS: duration of retention: 16.39 min; purity: 10095; MS (m/z): 468 (MA). 7.3.609 4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- Similar to the preparation of M44(3,4-ethylenedioxyphenyl)-2-fluoro-M2-(2-0h-(2piperazino)carbonylbenzofuran-5-yl -2,4-pyrimidinediamine hydrochlorium, M4-(3,4-homopinerazino)carbonylbenzofuran-5-| ethylenedioxyphenyl)»5-fluoro-M2-(24(M-htomopiperazinosecarbonylbenzofuraneZ-1l|»il|-2,4-pyrimidinediamine hydrochloride 72.4-pyrimidinediamine hydrochloride is obtained as a result of the reaction of M4-(3,4-(K926768) ethylenedioxyphenyl)-5-fluoro-M2-12-(M-tomoperazino)carbonylbenzofuran-5-1l1- and 2,4-pyrimidinediamine and hydrogen chloride. 1H NMR (0M5O-46 2 9.98 (B5, 1H), 9.05 (o) (5, INU, 8.18 (4, 1H, 724.8 Hz), 8.01 (8, INU), 7.58 (d, 1H, 2: 8.7 Gu, 7.50 (64, 18), 7.355, 1NU, 7.24 (4, IN, 1-24 Gy), 7.11 (49, 1H, Te Z tv 9 Hz), 6.80 (b, 1H, 1-87

Ty), 4.22 (5, 4), 4.20-3.650 (t, 8H), 3.20 (t, 2H); ЭХ/МС: duration of detention: 14.91 min; purity: 8695; MS (m/z): 505 (MN). 7.3.610 5-fluoro-M4-(3-hydroxyphenyl)-IM2-(2-(M- Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-12-0M- (se) piperazino) carbonylbenzofuran-5-yl|-piperazino)carbonylbenzofuran-5-yl1-2,4-pyrimidinediamine hydrochloride, 5-fluoro-2,4-pyrimidinedismine hydrochloride M44(3-hydroxyphenyl)-M2-/12-(M-pylerazino)carbonylbenzofuran - 5-yl|-2,4- (e») 2926502) pyrimidinediamine hydrochloride is obtained as a result of processing 5-fluoro-M4-(3-hydroxyphenia)-M2-(24(M-piperazino)carbonylbenzofuran-5-yl|- 2,4- "-pyrimidinediamine with hydrogen chloride "4M, dioxane). IN NMR (SOSZOYUKO 8.00 (5, 1H), 7.89 (5, 1), 7.98 (5, 1H), 7.60 (9. 1H, 7- 8.7 Gy), 7.45 (t , ZN), 7.16 2, 1H, 3-2 8.1 Go), 7.10 (t, 18), 7.02 (40, 1, 7-12 and 7.2 Gy), 6.70 (4 , 1H, 7- 2.4 and 8.4 Hz), 4.13 (t, s 4H), 3.37 (aHn, 3-54 Gy), 3.38 (04H, 1- 5.7 Gy) ; РХ/MS: retention time: 13.40 min.; purity: 7995; MS (m/z); 450 (MN). c 7.3.511 5-fluoro-M4-(3-hydroxyphenyl)-M2-|2-(M- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-H2-(M-piperazinomethylene)benzofuran- 5-Cyl|-piperazino)carbonylbenzofuran-5-yl)-2,4-pyrimidinediamine hydrochloride, 5-fluoro-2,4-pyrimidinediamine dihydrochloride 4-(3-hydroxyphenyl)-M2-(2-(M-piperazinomethylene)benzofuran-5 -1l|-7,4- (K926769) pyrimidinediamine dihydrochloride is obtained as a result of the reaction of 5-fluoro-MaA-(3-hydroxyphenyl)- M2-(2-(M-piperazinomethylene)benzofuran-5-1l|-2,4- " of pyrimidinediamine and hydrogen chloride (4M, dioxane). R/N NMR (SOSO 7 8.00 (4,

IN), 7.854, 180), 7.75 (t, ZN), 7.60 (pt, 201), 7.40-7.15 (t, 4H), 7.05 (5, 1H), 7, 00- in 6.800 (t, ZN), 4.65 (44, 2H), 3.60 (t, 8H). c 7.3.612 53-fluoro-M4-(3-hydroxyphenyl)-M2-13-(0M- Similar to the preparation of M4A-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(12-(M-t piperazino) carbonylmethyleneoxyphenyl|-|piperazino)carbonylbenzofuran-5-yl|-2,4-pyrimidinediamine hydrochloryl, 5-fluoro- and P. 2,4-pyrimidinediamine hydrochloryl. M4-(3-hydroxyphenyl). M2-(3-(M- piperazino)carbonylmethyleneoxyphenyl)-2,4- (85926773) pyrimidinediamine hydrochloride is obtained as a result of the reaction of 5-fluoro-M4-(3-hydroxyphenyl)-IH2-Y3-(M-piperazino)carbonylmethyleneoxyphene l|-7,4-pyrimidinediamine and hydrogen chloride (4M, dioxane). 1H NMR (SOZOVIS 7.994, 1H,

And 125.1 Sy), 7.29, 1H, 12 8.1 Hz), 7.21-7.05 (t, 5H)), 6.83 (40, 1H, 12: 2.4 and 8, 7 Hz), (ee) 6.77 a, 1), 4.79 (v, 2H), 3.83 (t, 2H)), 3.78 (t, 2H), 3.25 (t, 2NU ; LC/MS: retention time: 12.27 min; purity: 9199; MS (m/z): 439 (MN.M). kz 73.613 M2-13-(2-(M,M-) Similar to the preparation of M4-( 3,4-ethylenedioxyphenyl)-5-fluoro-m2-(2-(M-dimethylamino)styloxy|phenyl|-Ma-(3,4- piperazino)carbonylgonzofuran-5-yl-2,4-pyrimidinediamine hydrochloride, in shk ethylenedioxyphenia)-5-fluoro-7,4- as a result of processing M4-(3,4-ethylenedioxyphenyl). phenyl|-5-fluoro-2,4-pyrimidinediamine with an equivalent (8926771) amount of hydrogen chloride (4M, dioxane) gives M4-(3,4-ethylenedioxyphenyl)-M2-13-Y2-(M,M-dimethylamino)ethyloxy|pheny li-5-fluoro-2,4-pyrimidinediamine hydrochloride. LC/MS: retention time: 15.37 min; purity: 939; MS (m/z3): 426 (MH). 2 7.3.a214 ma4-(3, 5-dimethyl-4-hydroxyphenyl)-5- Similar to preparation M4-(3,4-styrenedioxyphenyl )-5-fluoro-1h2-(2-0M-fluoro-m2-13-12-(M-piperazino)carbonylbenzofuran-5-1l|-2,4-pyrimidinediamine hydrochloride, IM4-(3,5-morpholino)styloxy |phenyl|-2,4- dimethyl-4-hydroxyphenyl)-5-fluoro-M2-13-(2-(M-morpholino)ethyloxy|phenyl|-2,4- pyrimidinediamine hydrochloride pyrimidinediamine hydrochloride is obtained as a result of the reaction MA- (3,5-dimethyl-4-(K940256)hydroxyphenyl)-5-fluoro-M2-13-12-(M-morpholino)ethyloxy|phenyl)-2,4-pyrimidinediamine and hydrogen chloride (4M, dioxane). LC/MS: retention time: 15.78 min; purity: 9895; MS (Mie): 454 (MN); 1H NMR (0M50-ab: 10.60 (IN, 76 85), 9.58 (IN, 5), 8.29(1H, 5), 8.20 1H, 5), 7.43 (1H, 4 . , t), 4.05 (2H, t), 3.84 (4H, t), 3.55-3.50 (2H, t), 3.26 (2H, t), 2.25 (6H, 8) 7.3.,615 ma-(3-chloro-4-hydroxy-5-methylphenia)-5- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(2-(M-fluoro- m2-13-(24(0M-piperazino)carbonylbenzofuran-5-yl1-2,4-pyrimidinediamine hydrochloride, M4-(3-morpholino)styloxy|phenyl|-2,4-chloro-4-hydroxy-5-methylphenyl) -5-fluoro-M2-13-(2-(M-morpholino)ethyloxy Iphenyl|-pyrimidinediamine hydrochloride 2,4-pyrimidinediamine hydrochloride is obtained as a result of the reaction M4-(3-chloro-4- (5940269) hydroxy-5-methylphenyl )-5-fluoro-Mm2-|3-(2-(M-morpholino)ethyloxy|phenyl-2,4-pyrimidinediamine and hydrogen chloride (4M, dioxane). LC/MS: retention time: 14.74 min; purity: 9696; MS (m/z)y: 474 (Ma), 475 (MNE); IN NMR (OM5O-46: 10.03 (1H, 5), 9.35 (2H, 5), 9.06 (1H , 5), 8.171Н, 4, 12 3.9 Hn), 7.67 (IN, t), 7.52 ( IN, t), 7.46 PN, y, 72 8.7 Gy), 7.39 (IN, 5), 7.24(IN, 12 8.1 Go), 6.66 (IN, 9, 72 8, 1 Hz), 4.33 (1H, t), 4.07 (1H, 4, 22 13 Hz), 3.79 1 H, 6 1- 12.5 Hz", 3.56 (AN, tu, 3 .49 (AN, t), 3.29 (1Н, 5 7-12.5 Hz), 2.29 (ЗН, 5). 7.3.616 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|2-(M-

I3-(M-piperazino)carboniabenzofuran-5-111-2,4-pyrimidinedimine hydrochloride, in methylamino)carbonylstyleneoxyphenyl|- | as a result of treatment of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-13-(M-2,4-pyrimidinediamine hydrochloride methylamino)carbonylmethyleneoxyphenyl |-2,4-pyrimidinediamine with an equivalent amount (K926816) of hydrogen chloride (4M, dioxane) M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(M-methypamino)carbonylmethyphenoxyphenyl |-2,4-pyrimidinediamine hydrochloride is obtained. LC/MS: retention time: 17.04 min., purity: 9695, MS (m/z): 426 (MN), p

M4-4(3 4-ethylenedioxy)-5-fluoro-M2-172- M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(2-5) (hydroxymethyl)benzofuran-5- is placed in a dry reactor 1l1|-74- methoxycarbonylbenzofuran-2-yl)-2,4-pyrimidinediamine and carry out its reaction pyrimidinediamine (K926596) with diisobutylaluminum hydride (OV AN) (5 equivapents) in CH2CI2 at a temperature of -78 oC (supervision and control of the reaction is carried out with help

TLC), followed by treatment with a ferrous salt to obtain MA-(3,4-ethylenedioxy)-3-fluoro-M2-H2-(hydroxymethyl)benzofuran-z-1l1-2,4-se pyrimidinediamine. IN NMR (OM 50-a6):2 9.11 (5, IN), 8.02 (a, 1H, 72: 3.3 Hn), 7.96 (B1H, ze 1.8 Сy), 7.40- 7.30 (t, ZE), 7.19 (AK, 1H, 32 3.6 and 8.1 Gu), 6.78 (4, IN, 3- 8.7

GT), 6.59 (8, 1HO, 4.52 (4, 2H, 12: 5.1 Hn), 4.22 (5, 4NH; 19 NMR (0M5O-96); -46802; (e)

PH/MS: duration of retention: 19.14 min; purity: 9595; MS (m/z): 409 (MINE). 7.3.618 5-fluoro-M4-(3-hydroxyphenyl)-HM2-(2- Analogous to the preparation of M4-(3,4-ethylenedioxy)-5-fluoro-M2-(2-h-(hydroxymethyl)-"1H) -indol-5-yl|-2,4- (hydroxymethyl)benzofuran-5-yl|-2,4-pyrimidinediamine, 5-fluoro-M44(3-pyrimidinediamine (KU926700) hydroxyphenyl)-M2-(2-(methoxycarbon n) N)-indol-5-yl|-2,4-pyrimidinediamine is reduced with diisobutylaluminum hydride (RIVAI), obtaining 5-fluoro-M4-(3-hydroxyphenyl)-M2-(2-(hydroxymethyl)-"1H)- Indole-5-yl|-2,4-pyrimylindiamine. IN p

NMR (SOZOYUUP 7.81 (4, 1H, 4- 4.2 Gy), 7.23 (0, 1H, He 1.8 Go), 7.28-7.23 (t, ZNU, 7.19( 1H, 3-24 Gy), 7.12 (46, 1H, 72 1.8 and 9.0 Gy), 7.07 (, 1H, 1- 8.4 Hn), 6.52 (give, EN, I 1.2 and 8.E Gy), 6.30 (z, 1H)), 4.71 (z, 2); 192 NMR (SOZOI): -47971;

LC/MS: retention time: 15.36 min; purity: 10095; MS (m/1): 366 (MN). 7.3.619 5-fluoro-M2-|2- Analogous to the preparation of Ma-(3,4-ethidenedioxy)-5-fluoro-M2-(2" " "hydroxymethyl)benzofuran-5-yl-M4-14- | (hydroxymethyl)benzofuran-5-1l|-2,4-pyrimidinediamine, 5-fluoro-M2-(2-(isopropoxy)phenyl-2.4-pyrnimidindiamine | methoxycarbonylbenzofuran-5-1l)-h4-(4-isopropoxyphenyl)-2 ,4-pyrimidinediamine (K926705) is reduced with diisobutylaluminum hydride, obtaining 5-fluoro-m2-(2- - c (hydroxymethyl)benzofuran-5-yl1-IM4-(4-isopropoxyphenyl)-2,4-pyrimidineliamine.

IN NMR (SOZOBU C 783 (4, 1H, 1-33 Hu), 7.81 (v, PN), 7.59 (4, 2H, 1 90 Gy), p 7.298, 1H, 7: 9.0 Gy ), 7.22 (ab, IN, 2: 2.4 and 8.7 Gy), 6.84 (y, 2H, where 8.7 Hz), 6.56 (y, and IN, 1-12 Gy ), 4.64 (5, 2H), 4.56 (24, IN, 1-5.7 Gy), 1.31 (y, 6H, 1-- 6.0 Gy); 19E

Yam (SOZOr):-47926; РХ/MS: retention time: 21.03 min; purity: 9995;

MS (m/z): 409 (MN). 7.3.620 5-fluoro-Х2-(2- Similar to the preparation of M4-(3,4-ethylenedioxy)-5-fluoro-М2-(2-

Go! (hydroxymethyl)benzofuran-5-1l|-M4-(3- | (hydroxymethyl)benzofuran-5-yl|-2,2-pyrimidinediamine, 5-fluoro-M4-(3- hydroxyphenyl)-2,4-pyrimidinediamine hydroxyphenyl )-iM2-12-(methoxycarbonylbenzofuran-5-1l|-2,4-pyrimidinediamine (Kk926707) is reduced with diisobutylaluminum hydride, obtaining 5-fluoro-M2-(2- co (hydroxymethine)benzofuran-5-yl|-M4-(3 -hydroxyphenyl)-2,4-pyrimidinediamine 1H

NM (pM5O-a6): 2 9.37 (5, 1H), 9.17 (5, 19), 9.12 (5, 1H), 8.06 (4.1H, 15 3.9 g), koh 8.01 (0, 1H, 1.8 Gy), 7.41-7.35 (t, 2), 7.269, IN, 7-8, Hu, 711-705 (t, 2H), 20 6.60 (5, 1H), 6.51 (ai, IN, 7-2, and 8.4 Go), 5.1 (0 1 H, In 60 Go 451 (y, A, In 5.7 (Se) 42 ) ko 60 b5 ptn Gy); LC/MS: retention time: 16.21 min; purity: 9595; MS (m/z): 367 (MNK). 7.3.621 Mm4-(d-tert-butyl)phenyl)-5-fluoro-M2-|3- Similar to the preparation of M4-(3,4-ethylenedioxy)-5-Fluoro-M2-(2-(2-hydroxystyreneoxy) phenyl-2,4-(hydroxymethyl)benzofuran-5-1l|-2,4-pyrimidinediamine, M4-(4-tert-butylphenyl)-5-pyrimidinediamine (K925728) fluoro-M2-(3-methoxycarbonylmethyleneoxyphenia)-2, 4-pyrimidinediamine is reduced with diisobutylaluminum hydride, obtaining M4-(4-tert-butylphenyl)-5-fluoro-M2-(3-(2-tihydroxyethyleneoxy)phenyl|-2,4-pyrimidinediamine. IN NMR (SOSIZ Pi 7.94 ( ,

IN,2- 3.0 Go), 7.54 (0, 2H, 1:90 Hn), 7.37 (y, 2H, 1" 8.4 Hz), 7.29-7.35 (t IN ), 7.19-7.14 (t, 2H), 7.064, 1H, 1-81 Go), 6.824, IN, 2- 2.7 Hz), 6.57 (da, IN, 7: 2.4 and V Hz), 4.04-4.00 (t, ?2H), 3.93-3.89 (t, 2H), 1.33 (5, 90); 19E NMR (SOSIZU-47214; LC/MS: retention time: 22.39 min; purity: 9490; MS (m/z): 397 (MN), 70 7.3.622 5-(hydroxymethia)-m2-|3- (2- Analogously to the preparation of M4-4(3,4-ethylenedioxy)-5-fluoro-M2-|2- hydroxystylenoxy)pheniai-M4-(3-(hydroxymethyl)benzofuran-5-yl)-2,4-pyrimidinliamine, M4-(3-tihydroxyphenyl)-5-tihydroxyphenyl)-2,4-tyrimidinediamine methoxycarbonyl-M 2-(3-(methoxycarbonylmethyleneoxy)phenyl|-2,4-pyrimyldiamine (K926735) is reduced with lysobutylaluminum hydride, obtaining 5-(hydroxymethyl) -M2-II3- (2-hydroxyethyleneoxy)phenyl|-4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. IN NMR (SOZOru c 7.87(5.1H), 7.35 (IN, 2 1, 5 Gy), 7.15-7.08 (t, 5H), 6.57-6.50 (t, 2H), 4.56 (5, 2H), 3.92-3.86 (t, 2NI ), 3.84-3.79 (t, 2H); LC/MS: retention time: 1411 min; purity: 8962; MS (m/z): 369 (MN). 7.3.623 5-fluoro-M2- I3-0- Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-13-(2-(M- hydroxyethyleneoxy)phenyl|-1M4-43-morpholino)ethyleneoxy |phenyl|-2,4- of pyrimidinediamine, 5-fluoro-12-(34(2-isopr phenylphenyl)-2,4-pyrimidinediamine hydroxyethyleneoxy)phenyl|-M4-(3-isopropylphenyl)-2,4-pyrimidinediamine k940289 is obtained as a result of the reaction of 5-fluoro-Ma-(3-isopropylphenyl)-M2-(3-methoxycarbonylmethyleneoxyphenyl) -2,4-pyrimidinediamine with diisobutyl aluminum hydride, LC/MS: retention time: 23.03 min; purity: 9399; MS (m/z): 382 (Mk), 384 (MNK), IN NMR (Yum 50-46): 9.36 (1, 5), 9.24 (IN, 5), 8.20 1 H, d, 1-42 Gy), 7.851 H, 4, 3- 8.5 g), 7.57 (1H, 8), 7.41 (IN, 5), 7.33 (IN, 3-8.5 Hz), 7.17 1H, 6, 2-85 Hz), 7.05 (1H, 4, 3- 8.5 Hz), 6.56 1H, yes, 7- 8.5 Gu, 1-2 Hz) 4.94 (1H, in, 3-12 Hz), 3.94 (2H, 6 1-2 4.7 Gy), 3.76 (2H, pp), 2.95 (IN, sep 12 6 .9 Gn), 1.28 (6H, yes, 1-5 6.9 Gn, 2 0.6 Hz). 7.3.624 M4-(3-tert-butylphenia)-5-fluoro-M2-| )benzofur-25-1l|-2,4-morpholico)styreneoxy |phenyl|-2,4-pyrimidinediamine, M4-(3-tert-butylphenyl)-5-pyrimidinediamine K940287 fluoro-M2-12-(hydroxymethylene)benzofur- 5-yl|-2,4-pyrimidinediamine is obtained as a result of the reaction M4-(3-tert-butylphenyl)-5-fluoro-M2-(2-

Sh methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine with Ge) diisobutyl aluminum hydride. RH/MS; duration of detention: 23.15 min; purity: 99955; MS (m/z): 407 (MN.Yu); IN NMR (OM5O-46): 7 9.34 (1H, 8), 9.22 (1H, 8), 8.18 (an,a,21-3.9 Gk), 8.04 (1A, 5 ), 8.00 (IN, is, 3- 8.7 Hz), 7.60 (IN, 5, 2- 2.1 Go), 747 (СН, t), 7.34 (1Н, 2.15 : 7.8 Hz), 7.21 (IN, y, 3-8.7 Hz), 6.69 (1А, 5), 5.54 (IN, 6 1 5.8 ГІ), 4.63 ( 2H, 4, 2 5.8 Hz), 1.35 (9H, 5). (se) 7.3,625 5-fluoro-M4-43-isopropylphenyl)-M2-Y(2- Similar to the preparation of M4-(3,4-hethylenedioxyphenyl)-5-fluoro-M2-(3-12-(M- b hydroxymethylene|benzofur-5-1l|-2,4- morpholino)ethyleneoxy|phenyl)-2,4-pyrimidinediamine, 5-Fluoro-M4-(3-pyrimidinediamine K940286 isopropylphenyl)- M2-C(2-hydroxymethylene)benzofur- 5-yl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M4-(3-isopropylphenia)-M2-(2- or methoxycarbonylbenzofur-5-yl)-2,4-pyrimidinediamine with diisobutylaluminum hydride. LC/MS : retention time: 21.93 min; purity: se 9999; MS (m/z): 393 (MN); 1H NMR (PM5O0-46): 11 9.33 (1H, 5), 9.23 (IN, 5), 8.18 (IN, 0.3-3.9 Sy), 8.03 (1H, 5), 7.86 (18, f, 3-71 Hz), 7.57 (1H, 5) , 7.49 (2H, t), so 7.33 (an, II Gy), 7.05 (1H, a, 7-71 Hz), 6.69 (1H, 5), 5.54 (IN -5 5.7 Hz), 4.53 (2H. 4, 34- 5.7 Gy), 2.90 (IN, 5eri, 3- 6.9 Gy), 1.26 (CH, b, 7- 2 6.9 Hz). 7.3.626 MA-(3-tert-butylphenial)-5-fluoro-M2-|3- Similarly to preparation M4-(3,4 ethylenedioxyphenip)-5-fluoro-M2-(3-42- 4(M-(2-hydroxyethyleneoxy)phenyl)- 2,4-morpholino)ethyleneoxyphenyl)-2,4-pyrimidinediamine, Ma-(3-tert-butylphenyl)-5-pyrimidinediamine K940282 fluoro-M2-(3-(2-hydroxyethyleneoxy)phenyl|-2,4-pyrimidinediamine obtained as a result of the reaction of M4-(3-tert-butylphenyl)-5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine with diisobutylaluminum hydride, LC/MS: retention time: 21.63 min; purity: - c 9890; MS (m/z)y: 396 (M). ц 7.3.627 4.(3,4-bis(hydroxymethyl)phenyl|-5- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-I3-(24(M- and z» fluoro- M2-13-(2-morpholino)ethyleneoxy|phenyl|-2,4-pyrimidinediamine, M4-|3,4- hydroxyacetylenoxy)phenyl)-2,4- bis(hydroxymethyl)phenyl|-5-fluoro-ych2-| 3-(2-hydroxyethyleneoxy)phenyl-2,4-pyrimidinediamine (2940292) pyrimidinediamine is obtained as a result of the reaction M2-(3-ethoxycarbonylmethyleneoxyphenyl)-ma-(6-(3,3-dihydroisobenfuranyl-I-mono)|-5- fluoro-2,4-pyrimidinedismine with diisobutylaluminum hydride, LC/MS: duration

Go! retention: 13.06 min; purity: 10099; MS (m/z): 400 (ME). 7.3.628 (8935149); M2-(3,4-Stylenedioxyphenyl)- | 2-Chloro-5-fluoro-M4-(4-M(ethoxycarbon (dimethyl)methyl|phenyl|-M2-(3,4. ko M4-144(2-hydroxy»I,1- ethylenedioxyphenyl)-2,4 -pyrimidinediamine is reduced with 10 equivalents of dimethylethyl)phenyl|-5-fluoro-2,4-diisobutylaluminum hydride (1.0 M in toluene) at a temperature of 0 0E in -pyrimidinediamine dichloromethane. The reaction mixture is cooled by rapid absorption in methanol, the reaction mixture is dissolved in ethyl acetate, overcome an aqueous solution of a ferrous salt, stir at room temperature for 30 minutes with the addition of anhydrous sodium sulfate (Ce) (42) to 60 b5. The solution is filtered through celite and concentrated, and the concentrate is purified by column chromatography on silica gel, obtaining M2-( 3,4-ethylenelioxyphenyl)-M4-14-(2-hydroxy-1,1-dimethylethyl)phenyl|-5-fluoro-2,4-pyrimidinediamine. IN NMR (М 5О0-46):1 10.01 (Bg 5, EN), 9.6 (rs5, 11), 8.13 (4, 1H, 1:47 Hz), 7.58 (0, 2H, P- 8.2 Gy), 7.31 (4, 2H, 1- 8.8 Gy), 7.184, IN, 2- 2.3 Hz), 6.88 (04, IN, 7- 2.3 and 8.8 Hn), 6.73 4, 1H, 1 -88

Hz), 4.21-4.19 (ha, ANU, 3.56 (Bg 5, 2Н), 1.20 (8, 6Н); LC/MS: retention time: 29.34 min; purity: 9895; MS (Mazu 41 ("MNE 7.3,629 (K935151): 5-fluoro-m2-14-(2-hydroxy-1, 1- | Analogous to the preparation of IM2-(3,4-ethylenedioxyphenyl)-5-fluoro-M4- 14-(2-hydroxydimethylethyl)phenyl|-M4-(4-1,1-dimethylethyl)phenyl-2,4-pyrimidinediamine, ХМ2-14-4(1-ethoxycarbonyl-1-isopropoxyphenyl)-2,4- pyrimidinediamine|methyl)styliphenyl|-5-fluoro-M4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine is reduced with diisobutylaluminum hydride to form 5-fluoro-M2-(44(2-hydroxy-11-dimethylethyl)phenyl-M4-( 4-isopropoxyphenyl)-2,4-pyrimidinediamine. IN NMR (SrRSIZMO 7.894, 1H, 22.9 Gy), 7.46 (0, ZN, 32 8.8 Gy), 7.274, 2H, 1- 8.2 Hn ), 6.89 (4, 2H, 1- 9.3 Hz), 6.68-6.65 (t, NN), 4.53 (zero, IN, 7- 5.8 Gy), 3.57 (5, 2H), 1.36 (a, 6H, 1-5.8 Hu), 1.31 (z, 6H); LC/MS: retention time: 23.43 min; purity: 9995; MS (m /z): 4 (MH). 7.3.630 (2935153): 5-fluoro-M2-14-(2-hydroxy-1,1- | Similar to the preparation of M2-4(3,4-ethylenedioxy enyl)-5-fluoro-M4-|4-(2-hydroxy-dimethylethyl)phenyl|-M4-(3-1,1-dimethylethyl)phenyl|-2,4-pyrimidinediamine, M2-(4-(ethoxycarbonyl tihydroxyfenip )-2,4-pyrimidinediamine "dimethyl)methyl|phenyl)-5-fluoro-MCh4-(3-tihydroxyphenyl)-2,4-pyrimidinediamine is reduced with diisobutylaluminum hydride to form 5-fluoro-142-144(2-hydroxy-1, 1-dimethylethyl)phenyl |-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. IN NMR (CoSIZU:O 7.894, 1, 3- 2.9 Hz), 7.57 (5, IN 7.41 (4, 2H, 1- 8.5 Hn), 7.29 (8, 2H, 1582) tv, 1H, 1 -82 Go), 7.10 (a, 1, 3- 8.8 Go), 6.80-6.55 (t, 2H), 5.58 (5, 2H), 1.30 (5, 6H ); LC/MS: retention time: 18.01 min; purity: 98; MS (m/z): 369 (MN.v). 7.3.631 (K935154): M4-(3,4-ethylenedioxyphenyl)- | Similarly to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-fluoro-M4-14-(2-hydroxy-5-fluoro-Mm2-13-(2-hydroxyethoxy)phenyl|- 1,1-dimethylethyl)phenyl|- 2,4-pyrimidinediamine, M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine M24(33-methoxycarboniamethyleneoxyphenyl)-2,4-pyrimidinediamine is reduced with diisobutylaluminum hydride to form M4-(3,4-ethylenedioxyphenyl) -5-fluoro-M2-

I3-(-tihydroxyestoxy)phenyl |-2,4-pyrimidinediamine. IN NMR (SRSIZK C 7.88 (0, 1A, 1-38 g), 7.34 (0, IN, 15 2.3 g), 7.19 (48, 1H, 15 2.3 and 8.2. Hz ), 7.14 (0, 1H, 35 7.6

Hz), 7.01-5.97 (t, 2H), 6.84 (0, IN, 1- 8.8 Gy), 6.53 (44, 1H, 3- 1.7 and 7.6 Gy ), 4.26 (in,

YAN), 3.982, 14.1 Hz), 3.89 (. 2H, 22 4.1 Hz); РЧ/МС: retention time: average 18.36 min; purity: 9995; MS (m/z): 399 (MN.Yu). 7.3.532 (K935155): 5"-fluoro-m2-(4-(2- Analogously to the preparation of M2-(3,4-ethylenedioxyphenia)-5-fluoro-M4-(4-(2-hydroxy-thiproxyethoxy)phenia) -144-(3-1,1-dimethylethyl)phenyl)-2,4-pyrimidinediamine, 5-fluoro-M4-(3-hydroxyphenyl)-M2-(4-hydroxyphenyl)-2,4-pyrimidinediamine (methoxycarbonylmethyleneoxy)phenyl |-2,4-pyrimidinediamine is reduced by diisobutylaluminium hydride, obtaining 5 fluoro-142-|4-(2-hydroxyethoxy)phenyl-

M4-(3-tihydroxyphenyl)-2,4-pyrimidinediamine. IN NMR (SOSIZKO 7.73 (y, 1H, 3- 3.5 (Che)

Hz) 7.33 (4, 2H, ee 8.8 Hz), 7.15 (g 5, 1H), 7.04 (arr 5 2H, 1- 8.2 and 7.6 Hn), 6.78 (6, 2H, U- 8.8 Hz), 6.49 (9, IN, 2 7.6 Hyd), 3.95 (6, 2H, 32 4.7 Hz), 3.80 (6 2H, 1-5 4.7 Go);

VH/MS:. duration of retention: 14.49 min; purity: 9895; MS (m/z: 357 (MNK). (o) 7.3.633 (K935156): 5-fluoro-M2-|3-(2- Analogously to the preparation of M2-(3,4-ethylenedioxyphenia)-5-fluoro-M4 -(4 (2-hydroxy-hydroxyethoxy)phenyl-MA-(4-1,1-dimethylethyl)phenyl-2,4-pyrimidinediamine, 5-fluoro-M4-(4-isopropoxyphenyl)»h-isopropoxyphenyl)-2, 4-pyrimidinediamine M2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine is reduced with diisobutylaluminium trihydride, obtaining 5-fluoro-M2-13-4(2-hydroxyethoxy)phenyl|- sem 7y-(4-isopropoxyphenyl)-2,4- pyrimidinediamine. IN NMR (SOSIZU 0 7.90 (d, 18, 3- 3.5 Hz), 7.454, 2.1 8.8 Gy), 7.34 (18, 2-23 Hz), 7.13 ( 0 1H, 7- 8.2 Hz), 6.93 o (t, ZNU, 7.75 (3, 1H, 222.3 Gy), 6.52 (d0y, IN, I» 2.3 and 8, 2 Hz), 4.52 (zergeb, IN, I 5.7 g), 3.95-3.85 (t, 4H), 1.34 (y, 5H, 12 5.7 Gy); РХ/LMS : retention time : 21.17 min; purity: 9895; MS (m/z): 399 (MH). 7.3.534 (8935158): 5-fluoro-M4-(4-(2-tihydroxy-1,1- Similar to the preparation of M2-4(3,4-styrenedioxypheny)-5-fluoro-M4-14-(2-hydroxylmethylethyl)phenyl|-Mm2-(4-(2-1,1-limethylethyl)phenyl|-2 , 4-p yrimidineliamine, M4-(4-|1-ethoxycarbonyl 1" "hydroxyethoxy)phenyl|-2,4-methyl)stil|phenyl|-5-fluoro-M2-(4-methoxycarbonylmethyleneoxyphenyl)-72,4-pyrimidinediamine pyrimidinediamine is reduced by diisobutylaluminum hydride with the formation of 5-fluoro-14-(2-hydroxy-1,1-dimethylethyl)phenyl|-M2-(4-(2-hydroxyethoxy)phenial|-2,4-)pyrimidinediamine. IN NMR (SOS 7.83 (0, 1H, 1: 3.5 Gy, 7.49 (y, 2H, 12 8.8

Gy), 7.35 (d, 2H, 2- 8.8 Go), 7.31 (4, 2H, 32: 8.8 Go), 6.82 (4, 2H, 1- 8.8 Go) . РХ/MS: duration and R. retention: 16.86 min; purity: 9695; MS (m/z) in: 413 (ME). 7.3,635 (K935160): 5-fluoro-M2-(4402- Similar to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-fluoro-M4-|44(2-hydroxy-tihydroxyethoxy)phenyl|-M4-(4 - M -dimethylethyl)phenyl-2,4-pyrimidinediamine, 5-Fluoro-M4-(4-isopropoxyphenyl)-isopropoxyphenyl)-2,4-pyrimidinediamine M2(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine is reduced with diisobutylaluminum hydride, obtaining 5 -fluoro-M2-14-4(2-hydroxyethoxy)phenyl|- (ee) Mma-4-isopropoxyphenyl)-2,4-pyrimidineliamine. !/H NMR (0М50-а6): 1 9.128, 18), 8.92 (5, 1NI)), 7.98 (4, IN, 7: 3.5 Hz), 7.59 (8, 2Н, I: 8.8 Gy), 7.49 (y, 2H, Ie 9.3 Gy), co 6.86 (4, 7H, 1- 8.8 Gy), 6.76 (y, 2H, 2- 9.3 Hz), 4.82 (I, IN, 4-5 4.9 Gy), 4.55 (zeris,

IN, 2-64 Gy), 3.89 (i, 2H, 1- 5.3 Gy), 3.67 (arr 4, ?H, 1- 5.3 and 4.9 Gy), 1.24 ( 9, 6H, - TI 6.4 Hn); РХ/MS: retention time: 19.56 min; purity: 10095; MS (m/z): 399 (Ce) 42) co 60 b5 im 7.3.636 (8935161): 5-fluoro-ych4-(4-(2-tihydroxy-1,1- | Similar to the preparation of M2-43,4 -styrenedioxyphenyl)-5-fluoro-Ch4-14-(2-hydroxydimethylethyl)phenyl|-M2-13-(2-1,1-dimethylethyl)phenidi-2,4-pyrimidinediamine, M4-(4-(1 -ethoxycarbonyl-1-hydroxyethoxyphenyl)-2,4-methyl)stilphenyl|-5-fluoro-M2-(3-methoxycarbonylmethylphenyl)-2,4-pyrimidinediamine pyrimidinediamine is reduced with diisobutylaluminum hydride, obtaining 5-fluoro-M-(4-(2 -tihydroxy" 1,1-dimethylethyl)phenyl-M2-|3-(2-tihydroxyhetoxy)phenyl|-2,4-tyrimidinediamine. IN

YAM (0M50-46K2 9.27 (5.1), 9.11 (5, 1H), 8.07 (4, IN, 1- 3.5 Gy), 7.07 (d, 2H, 1- 8.8 0), 7.38-7.24 (t, 4), 7.065 (B 1H, 3- 8.2 Hz), 6.46 (ai, 18, 3- 8.9 Hyd), 4.83 and,

IN, 1-5.3 Hz), 4.66 (5, IN, 1-2 5.3 Gyu), 3.88 (6 2H, /- 5.3 Hz), 3.67 (0, IN, 32 5.3 Hz), 3.66 (6 1, 1- 5.3 Hz). 3.38 (0, 2H, 7: 5.3 Hz), 1.20 (5, "NU; LC/MS: retention time: 17.17 min; purity: 9695; MS (m/z)y; 413 (MNK). 7.3.537 (8935168): 5-fluoro-Ма4-14-(2-hydroxy-1,1- / Similar to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-fluoro-М4-(4- (2-hydroxydimethylethyl)phenyl|-M2-(4-1,1-dimethylethyl)phenyl|-2,4-pyrimidinediamine, M4-(4-(1-ethoxycarbonyl-1- isopropoxyphenyl)-2,4-pyrimidineliamine methyl)ethylphenyl|-5-fluoro-M2-(4-isopropoxyphenyl)-2,4-pyrimidinediamine is reduced with diisobutylaluminum hydride, obtaining 5-fluoro-M4-|44(2-hydroxy-1,1-dimethalethyl)phenyl|-M2- (4-isopropoxyphenia)-2,4-pyrimidinediamine.IN NMR (0M5O-abu:i 9.21 (in, 1H), 8.93 (5, 1H), 8.00 (4, IN, 2- 4, 1 Sy), 7.62 (y, 2H, 1- 8.8

Gy, 7.48 (9, 2H, 2- 8.8 Hz), 7.27 (4, 2H, 1-5 8.8 Hn), 6.75 (4, 2H, I 8.8 Gy), 4.65 (and,

IN, 1- 5.3 Hz), 4.47 (zerieb, 1H, 2- 5.8 Hz), 3.38 (y, 2H, 1- 5.3 Hz 1.22 (y, 5H, 1 5 ,8

Hz), 1.20 (in, 6H); LC/MS: duration of absorption: 22.97 min; purity: 9995; MS (m/z):

A (МН. 7.3.638 (8935179): 5-dugor-M4-13-(2- Similar to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-fluoro-M4-H14-(2-hydroxy-hydroxyethoxy)phenyl |-M2-(3-1,1-limethylethyl)phenyl|-2,4-pyrimidinediamine, 5-fluoro-M2-(3-hydroxyphenyl)-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine methoxycarbonylmethyleneoxyphenia)- 2,4-pyrimidinediamine is reduced with diisobutylaluminum hydride, obtaining 5-fluoro-M4-13-(2-hydroxyethoxy)phenyl|-142-(3-hydroxyphenyl)-2,4-pyrimidinediamine. IN NMR (PM50-46:E 9.23 (5, 1H), 9.14 (5, 1H), 9.06 (5, 1H), 8.07 (d, 18, 32: 4.1 Co), 7.51 (49, 1, 15 1 ,7 and 7.6 Hz, 7.30 (arr 1, 1-2 2.3 and 1.7 Cm), 7.19 (i, 1H, le 8.2 Hz), 7.13 (B 5, 1H)U, 7.11 (t, 1), 6.96 (IN, - 7.6 Gy), 6.61 (49, EN, 1- 2.3 and 8.2 Gy), 6.28 ( 4, 1H, /- 2.3 Hz and 8.2 Hn), 484(B1H,1- 5.8 Sk), 3.92 (i, 7H, 1- 5.2 i), 3.68 (arr Phi, 2H, 1- 5.2 Ha); RF/MS: retention time: 14.71 min; purity: 969; MS (m/z): 357 (MN), 7.3.639 (K935171): 5-fluorine -M2-|4-(2-hydroxy-I,1- | Similar to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-ft or-M4-(4-(2-hydroxydimethylethyl)phenyl|-M4-(3-1,1-dimethylethyl)phenyl|-pyrimidine-2,4-diamine, M44-14-(1-ethoxycarbonyl-1- hydroxyphenyl)-2,4-pyrimidinediamine methyl)ethyl)phenyl|-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine are reduced with diisobutylaluminum hydride, obtaining 5-fluoro-M2-14-(2-hydroxy -1,1- o dimethylethyl)phenyl-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 14 NMR (0M5O- ab 9.24 (5.1), 9.13 (5, IN), 9501 (5, 1H), 8.04 (8, 10, 7- 3.5 Hz), 7.68 (90, 2H, 32 8.8 Hz), 7.29 (4, 2H, 1-2 8.8 Hz), 7.16 (bg 5, 1H), 7.07 (t, 1H), 6, 94 (I, IN, 8.8 Gy), 6.30 (t, 1H), 4.64 (5 1H, 12: 5.8 y), 3.38 (9, 211, 722 5.3 Hyd) . -M2-14-(2- Analogously to the preparation of IM2-(3,4-styrenedioxyphenyl)-5-fluoro-M 4-4 (2-hydroxy-tihydroxyethoxy)phenyl| M4-(2-1,3 "dimethylethyl)phenyl| -2,4-pyrimidinediamine, M2-(2-carbomethoxybenzofur»5-yl)»b tihydroxymethylbenzofur-5-1l)-2,4-5-fluoro-ShM4-44-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine pyrimidinediamine is reduced with diisobutylaluminum hydride , giving 5-fluoro-M2 |4-(2-hydroxyethoxy)phenyl)-M2-(2-hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine. 11 or:

NMR (pM5O0-4bu:s 9.26 (5, 1H), 8.94 (5, 1H), 8.01 (y, 1H, 2: 4.1 U, 7.99 (5, IN), 7 ,52-7.45 (t, 4H), 6.72 (d, 2H, 1- 9.3 GB), 6.66 (5, 1H), 5.46 (5, 1H, 2-5 5, 3 Gi), 4.82 (, urine

IN, 1: 5.8 Gy), 4.55 (y, 7H, 12: 5.8 Hz), 3.89 (t, 2H, 12 5.3 Gy), 3.67 (arr 4, 2H, 7 5.3

Hz); RF/MS: retention time: 14.97 min; purity: 9195; MS (m/z); 41 (I HAVE). so 7.3.641 (8935176): M2-(3,4-ethylenedioxyphenyl)- | Similar to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-fluoro-M4-|4-(2-hydroxy-5-fluoro-ma-(3-(2-hydroxyethoxy)phenyl|- 1,1-dimethylethyl)phenyl |-2,4-pyrimidinediamine, M2-(3,4-ethylenedioxyphenyl)-5-fluoro-2.A-pyrimidinediamine Ma-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine is reduced with lysobutylaluminumhydryl, obtaining M2-(3,4 -ethylenedioxyphenia)-3-fluoro-M4-13-(2-hydroxyethoxy)phenyl-2,4-pyrimidinediamine.. IN NMR (PM5O-y6):0 9.22 (z, 1H), 8.98 (5, IN), 8.05 (4, IN, 2- 3.5 Hz), 7.47 (49, 1H, 2: 1.1 and 8.2 Gy), 7.27 (, 1H, « 1-2 1.7 Hz), 7.23 (0, 1H, 122.3 Hz) 7.18 1, re 8.2 Gy), 7.05 (84, IN, 152.3 and 8.8 Gy), 6 .68 (8, IN, 2- 8.2 Go), 6.61 (94, 1, 2: 1.7 and 8.8 Hz), 4.85 (1, IN, 3- 53 Gy), shsh 4.18-4.14 (t, AN), 3.91 (i, 2H, 7- 5.3 Hz, 3.68 (d 2H, 7- 5.3 Gu; RHUMS: s duration of retention: 17, 35 he; purity: 9298; MS (m/z): 399 (MNK). p » 7.3.542 (8935177): 5-fluoro-M2-14-(2-hydroxy-) Similar to the preparation of 1Ch2-(3,4- ethylenedioxyphenyl)-5-fluoro-I44-(4-(2-hydroxy-p1,1,dimethylethyl)phenyl )-Ma-(2-11-dimethylethyl)phenyl)|-2,4-pyrimidinediamine, M4-(2-carbomethoxybenzofur-5-1p)-hydroxymethylbenzofur-5-1l)-2,4- M2-14-(1 -ethoxycarbonyl-1-methyl)stilphenyl|-5-fluoro-2,4-pyrimidinediamine pyrimidinediamine is reduced with diisobutylaluminum hydride, obtaining 5-fluoro-M2-(14-(2-hydroxy-1,1 dimethylethyl)phenyl)Ma-(2- hydroxymethylbenzofur-5-yl)-2,4-pyrimidinediamine.

PH/MS: retention time: 18.17 min; purity: 9490; MS (m/z): 423 (MNE). so 7.3.643 (8935178): 5-fluoro-M2-13-02- Analogous to the preparation of M2-(3,4-ethylenedioxyphenyl)-3-fluoro-Mm4-/4-(2-hydroxy-hydroxyethyloxy)phenyl|-M4 -(2-1,1-dimethylethyl)phenyl-2,4-pyrimylinliamine, M4-(2-carbomethoxybenzofur-5-yl)- co hydroxymethylbenzofur-5-1l)-2,4-5-fluoro-M2-(3 -methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine pyrimidinediamine is reduced with diisobutylaluminum hydride, obtaining 5-fluoro-M2-(342-sh hydroxyethyloxy)phenyl-Ch4-(2-hydroxymethylbenzofur-5-1l)-2,4-pyrimidinediamine. (Se) 42) ko 60 b5

1H NMR (0M50-46):11 9.93 (5, 1), 9.12 (5, 18), 8.07 (8, 1H, 2-- 3.6 Go), 8.01 (9, 1H, 122.3 Gu), 7.55-7.46 (t, 2H)), 7.29 (be 5, IN), 7.23 (y, IN, 22 8.2 Hz), 7.03 (, 1H, 12 8.2 Hz), 6.58 (5, 1H), 5.44 (dp, IN, 2- 2.3 and 8.2 Hz), 5.47 (6, IN, 1" 5.8 Hz), 4.80 (th,

IN, /e 5.3 Gy), 4.55 (4, 2H, 2-5.3 Sp). 3.8 (di 2, 7 5.3 Hz), 3.63 (46, 2H, 2-5 5.3

Hz); РХ/MS: retention time: 15.41 min; purity: 8895; MS (m/z): 411 (MN). 7.3.644 (8935181): M4A-(3,5-dimethoxyphenyl)-5- Similar to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-fluoro-M4-14-(2-hydroxy-fluoro-M2-134( 2-hydroxyethoxy)phenyl)-2,4- | 1,1-dimethylethyl)phenyl-2,4-pyrimidinediamine, M4-(3,5-dimethoxyphenyl)-5-fluoro-M2- pyrimidinediamine (3-methoxycarbonylmethyleneoxyphenia-2,4-pyrimylinamine is reduced with diisobutylaluminum hydride, obtaining M4-(3, 5-dimethoxyphenyl)-5-fluoro-M2-(3-(2-hydroxyethoxy)phenyl|-2,4-pyrimidineliamine. IN NMR HOM5O-Y6X:P1 9.24 (5, 18), 9.18 (5, 1NU, 8.11 (4, 1H, 1-5 3.5 Hz), 7.31-7.26 (t, ?2H), 7.059, 1H, 5 8.2 Hn), 6.99 (and 18 ,3: 2.3 Gy), 6.43 (ad, 1H, 1-23 Hz, 8.2 Hz), 6.20 0, 1H, 3- 2.3 Gy), 4.89 (6 IN,

I-5.8 Gy), 3.83 (, 2H, 1-5.3 Gy), 3.67 (in, 6H), 3.66-3.60 (t, 2H); LC/MS: retention time: 18.78 min; purity: 9592; MS (m/z): 400 (MN). 7.3.645 ("K935183); 5-fluoro-M2-(4-(2- Analogously to the preparation of M2-(3,4-styrenedioxyphenyl)-5-fluoro-M4-i4-(2-hydroxy-hydroxyethoxy)phenyl|-M4-(3,4- 1 ,1-dimethylethyl)phenyl|-2,4-pyrimidinediamine, 5-fluoro-h2-(4-propylenedioxyphenyl)-2,4-(methoxycarbonylmethyleneoxy)phenyl|-M4-(3,4-propylenedioxyphenide)-2,4- tyrimidinediamine pyrimidinediamine is reduced with diisobutylaluminiumhydryl with the formation of 5-fluoro-

32-(4-(2-hydroxyethoxy)phenyl|-M4-(3,4-propylenedioxyphenyl)-2,4-pyrimidinediamine. H NMR (0M50-6):01 9.15 (5, 1H), 8.97 (5, 1H), 8.00 (I, 1 H, z- 3.5 Hz), 7.499, 2H; 15 8.8 Gy), 7.40-7.31 st 2), 6.88 (40 , IN, 12 8.8 Gy), 6.80 (0, 2H, 1-8.8 Hz), 4.82 0, EN, 7- 5.3 Gy), 4.1254.04 (t AN) . ; LC/MS: retention time: 17.05 min; purity: 9695; MS (m/z): 413 (MN). 7.3.646 (935186): 5-fluoro-M2-1442- Similar to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-fluoro-M4-(4(2-hydroxy-hydroxyethoxy)phenyl|-M44(3,4 - 1,1"dimethylethene)pheny|-2,4-pyrimidinediamine, 5-fluoro-M2-|3-propylenedioxyphenyl)-2,4- (methoxycarbonylmethyleneoxy)phenyl|-M4-(3,4-propylenedioxyphenyl)-2, 4- ! pyrimidinediamine pyrimidinediamine is reduced with diisobutylaluminum gylryl to form 5-fluoro-2-(3-(2-hydroxyethoxy)phenyl|-Ch4-33,4-propylenedioxyphenyl)-2,4-pyrimidinediamine. IN NMR (0M50-46): SI 9.21 (5, 1H), 9.14 (5, 1H), 8.07 (y, 1H, 3-2 3.5 Hz), 7.42-7, 36 (t, 2H), 7.29-7.24 (tt, 2H), 7.07 (0 1H, 1-82 Gy), 6.900, 1H, 12 8.8 13), 6.45 (00, 18, - 1.7 and 8.3 Gy), 4.82 (1, IN, 2- 5.3 Gy), 4.12-4.04 (arr 4, 2H, 12: 5.3 Sy), 3.86 J, 2H, 12: 5.3 HC), 3.67 (arr 4, 2H, 7: 5.3 Hyd), 2.07 (d, 2H, 2- 5.3 Sy);

PH/MS: retention time: 17.95 min; purity: 9625; MS (m/z): 413 (MIN). high school

M4-(4-tert-butylphenyl)-5-fluoro-M2- Ma-(4-tert-butylphenyl)-5-fluoro-M2-(2,3-digylro-2-(carboxy)benzofuran-o-yl1- 2,4-

I(2,3-digylro-2-(carboxy)benzofuran-5-pyrimidinediamine is obtained as a result of the reaction M2-(2-tert-butylphenyl)-5-fluoro»-yl|-2,4-pyrimidinediamine (K926720) M2 -(2,3-digylpro-2-(methoxycarbonyl)benzofuran-5-yl|-2,4-pyrimidinediamine and lithium tetraoxide PLON) IN TNE:HO2O at room temperature. 18 NMR (0M50-а6):0 10.01 (65, 18), 9.69 (05, 18), 8.13 (9, NE, 7- 4.85 Г and), 7.57 (0, 2Н, 2 8.7 Hz), 7.50 (8.1), 7.354, 2, 1 8.1 Sy), 7.13 (4, 1H, 1-8.7 Hz), 6.75 (b, 1H, 1-90 Gy), 5.21 (44, 1H, /-: 6.3 and 19.5 Hz), 3.49 (44, IN, 110.5 and 16.5 Hz), 3.17 (give, 1H, 1- 6.6 ( se) and 16.5 Hz), 1.27 (in, 9H); RC/LMS: duration of retention: 22.53 min; purity: 9395;

MS (m/z): 423 (Mn. (o) 7.365648 M4-(4-tert-butylphenyl)-M2-(3- Analogous to the preparation of M4-(4-tert-butylphenyl)-5-fluoro-M2-12, 3-dihydro-2-carboxymethyleneoxyphenyl)-5-fluoro-2,4- | KO26726) M24(3-carboxymethyleneoxyphenyl)-2,4-pyrimidinediamide is obtained as a result of the reaction of M4-(4-tert-butylphenyl)-5-fluoro-M2-(3-methoxycarbonylmethyleneoxypheny)-sem 2,a-pyrimidinediamine and lithium hydroxide. IN YAM? (YUM50-a6):2 12.88 (B5, 18), 9.29 (5, NO), 9.16 (5, 1NU, 8.07 (4, IN, I: 3.3 Gi ), 7.68 (a, 26, 3-8.7 Hz), 7.35-7.31 so (t, ZNI), 7.26 (d, 1H, 32 8.4 Gy), 7.06 (i , IN, 7: 8.4 Gy), 6.41 (yes, 1H,, 42.4 and 84

Hz), 4.54 (5, 2H), 1.27 (8, UN); 19E NMR (PM5О0-46):-46463; ВХ/МС: duration of retention: 22.94 min; purity: 975; MS (m/z): 411 (MN). 7.3.649 5-fluoro-M2-13- Similar to the preparation of M4-(4-tert-butylphenyl)-5-fluoro-M2-I2,3-dihydro-2-(carboxymethyleneoxy)phenyl-M4-H4-(carboxy)benzofuran -5-yl|-2,4-pyrimidinediamine, 5-fluoro-M24(3- "(isopropoxy)phenyl-2,4-pyrimidinediamine 1 carboxymethyleneoxyphenyl)-444(4-isopropoxyphenia)-2,4-pyrimidinlismine (K926731) is obtained as a result of the reaction of 5-fluoro-M2-(3-methoxycarbonylethyleneoxyfenip)- -in

Ma44-isopropoxyphenyl)-2,4 lyrimidinediamine and lithium hydroxide. YIN YAM? c (rm5o-abuko 6.19(b5, 1), 9.01 (5, 1), 8.02 (4, 1H, 7- 3.9 Gy), 7.63 (4.2, 1- 9 ,3

Hn), 7.19-7.14 (t, 2H)), 6.96 (i, 1H, 1-8.7 Gy), 5.87 (8, 2H, 19.6 Hz), 65.28 (49.18, p 1-2.A5 and 9.0 Gy), 4.56 (24, 1H, I: 6.6 Hz), 3.94 (in, 2H), K.24 (0, 6H , 7-6.6 Hz); и » РХ/MS: retention time: 20.13 min; purity: 10096; MS (m/z): 413 (MNK). 7.3.650 2,M4-bis(4-carboxymethyleneoxy)phenyl- | Similarly to the preparation of M4-(4-tert-butyphenyl)-5-fluoro-M2-(2,3-dihydro-2-5-fluoro-2,4-pyrimidinediamine (2926560) (carboxy)benzofuran-5-yl|-2 ,4-pyrimidinediamine, M2,IM4-bis(4-carboxymethyleneoxy)phenyl-5-fluoro-2,4-pyrimidinediamine is obtained as a result of hydrolysis of M2.M4-bis(4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-2 ,4- pyrimidinediamine and MON. IN NMR (SOZOYUKO 7.86 (05, 1), 7.55 (y, 2H, 1-90

Hz), 7.32 (Ba, 28, 2: 9.3 Hz), 6.95 (t, 4H), 4.56 (5, 2H), 19E YAMRE (SOSIZ):-21852; for RH/MS: retention time: 15.16 min; purity: 7795; MS (m/z): 429 (MIC). koch M243-carboxymethyleneoxyphenyl)-Ma4- Similar to the preparation of M4-(4-tert-butylphenia)-5-fluoro42-12,3-dihydro-2-(3,4-styrenedioxyphenyl)-5-fluoro-2,4-carboxy benzofuran-5-yl|-2,4-pyrimidinediamine, M2-(3-shk (Се) 42) ko 60 b5 pyrimidinediamine (K926483) carboxymethylevoxyphenyl)-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2 ,4- pyrimidinediamine is obtained as a result of the reaction of M2-(3" ethoxycarbonylmethyleneoxyphenyl)-M4-(3,4-styrenedioxyphenyl)-5-fluoro-2,4- tyrimidinediamine and ION. 1H NMR (YUM50-462:0 12.90 (5, 1), 9.20 (5, 2H)), 8.05 (0.1, and 132 Hu), 7.32-7.21 (t, ЗН), 7.О8(1Н, 3-81 7), 6.80 (0, 1Н, 37-8.4 Го), 6.А0(49.1Н, 1 1.8 and 8.2 Ги), 4.53 (5, 2H), 4.20 (5, 4H); LC/MS: retention time: 18.26 min; purity: 10095; MS (m/z): 413 (MN). 7.3.052 M2-(3-carboxymethyleneoxyphenyl)-5- Similar to the preparation of M4-(4-tert-butyphenyl)-5-fluoro-yM2-(2,3-dihydro-2-fluoro-m4-(3-hydroxyphenyl)- 2,4-(carboxy)benzofuran-5-1l1-2,4-pyrimidinediamine, M2-(3-pyrimidinediamine (8945126) carboxymethyleneoxyphenyl)-5-fluoro-M4-(3-tihydroxyphenyl)-2,4-pyrimidinediamine is obtained in as a result of the reaction of 5-fluoro-M4-(3-hydroxyphenyl)-M2-(3-(methoxycarbonylmethyleneoxyphenyl-2,4-pyrimidinediamine) and PON. 18 NMR (0М50-46):5 4.55 (5, 2Н)), 6 ,43 (49, 1-2,1,8,1 Hz, 1), 6,48 (49,32 21 and 7,2 Gu,

TNU, 7.06-7.13 (t, ZNU, 7.28-7.34 (t, Z), 8.09 (y, 72 3.6 Hz, 1H), 9.22 (ve, 1H) . ; MS (m/z)y: 370.63 (MH). 7.3.553 M2-(4-carboxymethyleneoxyphenyl)-M4- Analogously to the preparation of 1M4-(4-tert-butylphenyl)-5-fluoro-M2-|2, 3-dihydro-2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-(carboxy)benzofuran-5-yl|-2,4-pyrimidinediamine, M2- pyrimidinediamine (KO26238) (carboxymethyleneoxyphenyl)-M4 -(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M2-(4-stoxycarbonylmethyleneoxyphenyl)-M4-(3,4-ethylenelioxyphenyl)-5-fluoro-2,4-pyrimidinediamine and OH. 1H NMR (0M50-46K:0 8.16 (d, 1H, 124.8 Gy), 7.37 (va, 2H, 15 9 Gy), 7.25 94, 1H, 1- ЗНа), 7.08 (tp, 1H), 6.83 (t, ZN), 4.64 (5, 214), 4.23 (5, 4H); LC/MS: retention time: 19.15 min; purity: 10095; MS (m/z): 413 (MmNU. 7.3.654 M2-(4-carboxymethyleneoxyphenyl)-5- Similar to the preparation of M4-(4-tert-butylphenyl)-5-fluoro -M2-(2,3-dihydro-2-fluoro-M4-(3-hydroxyphenyl)-2,4-(carboxy)benzofuran-5-yl-2,4-pyrimidinediamine, 5-fluoro-M2-(4- Pyrimidinediamine (K926564) carboxymethyleneoxyphenyl)-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of processing 5-fluoro-M2-(4-ethoxycarbonylmethyleneoxyphenyl)-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine PON . IN NMR (СО3О0:О 7.89 (4, IN, 12 5.1 Hz), 7.3444, 2H, 1-21 and 9.3 Go), 7.19-7.08 (t, 2NI), 6.98 (44, 2H, 1: 2.4 and 8.4

Hp), 6.69 (3, NO), 4.68 (5, 2H); ISE NMR (СО3О0);-21860; PH/MS: duration of retention: 15.69 min; purity: 9995; MS (m/z): 371 (MN cu.

M24(2-carboxybenzofuran-5-yl)-5-fluoro- | Similarly to the preparation of M4-(4-tert-butylphenyl)-5-fluoro-M2-(2,3-dihydro-2-se 1M4-(3-hydroxyphenyl)-2.4-n (carboxy)benzofuran-5-yl-2, 4-pyrimidinediamine, M2-(2-carboxybenzofuran-5-pyrimidinediamine (2926478) yl)-5-fluoro-M4-(3-hydroxyphenia)-2,4-pyrimidinediamine is obtained as a result of processing 5-fluoro-Mm4-(3 -hydroxyphenyl)-M42-(2-methoxycarbonylbenzofuran-5-iya)-4- pyrimidinediamine ION. 1H NAM (SOSOJI 7.97 (Ba, 2H), 7.60-7.44 (t, 48), 7, 20-7.05 (tt, ZNU), 6.69 (v, INU; 92 NMR (SOZOI):-21844; RH/MS: retention time: 16.77 min; purity: 10095; MS (m/z) : 381 (MEN). "c 7.3.656 M2-(2-carboxyindole-5-1l)-5-fluoro-M4-(3- | Similar to the preparation of M4-(4-tert-butylphenyl)-5-fluoro-M2 -(2,3-dihydro-2-hydroxyphenyl)-2,4-pyrimiddiamine (carboxy)benzofuran-5-11|-2,4-thyrimidinediamine, M2-(2-carboxyindole-5-1l)-5- (K926479 ) fluoro-Mα-3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of processing (22) 152-(2-ethoxycarbonylindol-5-yl)-5-fluoro- M4-(3-hydroxyphenyl)-2,4- pyrimidinediamine hydroxide lit ium (ION). YIN YAM? (СО3ОЮ):0 7.83 (t, 1H), che 7.73 (v, 1), 7.50 (Ba, IN, I- 8.7 Gy), 7.30-7.11 (t, 5H), 6.68 (By, 1); PH/MS: retention time: 16.50 min; purity: 9790; MS (m/z): 380 (MN). se 7.3.657 Ma4-(4-tert-butylphenyl)-M2-(2- Similar to the preparation of M4-(4-tert-butylphenyl)-5-fluoro-M2-12,3-dihydro-2-carboxybenzofuran-5-yl )-5-fluoro-2,4-(carboxy)benzofuran-5-yl|-2,4-pyrimidinediamine, M4-(4-tert-butylphenia)-M2-(2-(ee)pyrimidinediamine (K926481) carboxybenzofuran- 5-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of processing mA-(4-tert-Butylphenyl)-5-fluoro-M2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine PON . IN NMR (SOZOI:O 9.3 (84, 2HB, 8.25 (5, 1H), 8.10 (c, 18), 7.65-7.30 (t, 5H), 1.25 (5 , 9H); 19E NMR (SUZOIU):-21844; LC/MS: retention time: 23.32 min; purity: 10099; ME (m/z): 421 (MNK). " 7.3.658 M4-(3- tert-butylphenyl)-M2-(3- Analogously to the preparation of 144-(4-tert-butylphenyl)-5-fluoro-M2-(2,3-dihydro-2" carboxymethyleneoxyphenylI-5-fluoro-2,4- | (carboxy )benzofuran-5-yl|-2,4-pyrimidinediamine, Ч4-(3-tert-butylphenyl)-М2-(3- sshch pyrimidinediamine 940230 carboxymethyleneoxyphenyl)-5-fluoro 2,4-pyrimidinediamine is obtained as a result of the reaction of 4- (3-tert-butylphenyl)-5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenia)-2,4-pyrimidinediamine and MON. LC/MS: retention time: 23.61 min; purity: "z 9995; MS (m/z) : 410 (Mk), 412 (MH); IN NMR (OM5O0-46):0 9.45 (1H, 5), 9.33 (IN, k 5), 8.21 (IN, I, 2- 3 .9 Hz), 7.98 (IN, y, 2 6.6 Hz), 7.60 (1, 6 1-2 Gy), 7.44-7.34 (ZN, tu, 7.24-7.15 (24, t), 6.54 (1H, d, 12: 7.85 Ho), 4.68 (2H, 5), 1.36 (9H, 5). 7.3.659 M2-(3-carboxystylenaminophenyl) -M4- | As a result of the 1Ch2-(3-ethoxycarbovylmethyleneaminophenyl)-M4-(3,4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-ethylenedioxyphenyl)-5-fluoro-2,4-pnyrimidinediamine (0.1 g) and LON (10 equivalents) (ee) pyrimidineliamine (K950190) In MeOnH:HO I: 1, by volume) for 1 hour at room temperature, followed by treatment with hydrochloric acid, a solid is formed.

Kkz The obtained solid substance is filtered, washed with water and dried, obtaining M2-(3-carboxymethyleneaminophenyl)-M4-(3,4-ethylenedioxyphenyl)-5- - fluoro-2,4-pyrimidinediamine, LC/MS: retention time: 18, 23 minutes; purity: 87.695; MS (m/z); 41201 (MN). to ask (Se) (42)

F) ko 60 b5

7.3.550 M2-(carboxymethyleneaminophenyl)-5- Similar to the preparation of M2-(3-carboxymethyleneaminophenyl)-Ma-(3,4-fluoro-M4-I3-(2-hydroxyethyloxy)phenyl|- ethylenedioxyphenyl)-5-fluoro-2 ,4-pyrimidinediamine, M2- 2,4-pyrimidinediamine (К950230) "carboxymethyleneaminophenyl)-5-fluoro- M4-|3-(2-hilroxystyloxy)fevia|-2,4- pyrimidinedismine is obtained as a result of hydrolysis of M2-(stoxycarbonylmethyleneaminophenyl) -5-fluoro-M4-13-(2-hydroxytylenoxy uphenyl|- 2,4-pyrimidinediamine and 14OH. LC/MS: retention time: 12.15 min; purity: 78.395; MS (m/z): 413.01 ( MN 7.3.661 5-fluoro-M4-I3-022- Mixture M2-(carboxymethyleneaminophenyl)-5-fluoro-144-13-(2-hydroxyethylamino uphenyl|-M2-(13-1M-(2- hydroxyethylamino)phenyl) |-2,4-pyrimidinediamine (10 mg), 2-aminostanol (10 hydroxyethylamino)|carbonylmethylene |) equivalents) and RuBgoR (7 equivalents) are stirred in 0.5 ml of DMF for 24 nophenyl|-2,4-pyrimidinediamine (8950231 ) | hours at room temperature. The mixture is dissolved in water, extracted with RIOAc, the organic phase is dried over M e5O4. The solvent is removed under reduced pressure, 706 and the precipitate is subjected to column chromatography on silica gel (SNCI.Z: Acetone, 2: |), obtaining 5-fluoro-IM4-1342-tihydroxyethylamino)phenyl)|-M2-13-Pch4-42- hydroxycylamino )|carbonylmethyleneaminophenyl|-2,4-pyrimidinediamine. LC/MS: retention time: 12.98 min; purity: 92.60; MS (m/z); 455.97 (MN). 7.3662 M24340Msh-2- Analogously to the preparation of M4-(3-(2-hydroxystilamino)phenyl|-42-(3-144(2- aminostilamino)carbonylmethyleneaminof | hydroxyethylamino)|carbonylmethyleneaminophenyl|-5-fluoro-2,4-pyrimidinediamine, enyl |-5-fluoro-MA4-(3-O2-M2-I34(M-2-aminoethylamino)carbonylmethyleneaminopheni)-5-fluoro-MA-13-(2-hydroxyethyleneoxy|phenyl-2,4-hydroxyethyleneoxy)phenyl| -2,4-pyrimidinediamine is restrained as a result of the reaction of pyrimidinediamine (K9507232) 142-(carboxymethyleneaminophenyl)-5-fluoro-Ma-|34(2-hydroxystylamino)phenyl|-2,4- tyrimidinediamine and 1,2-ethylenediamine. РХ/ MS: retention time: 11.31 min; purity: 93.595; MS (m/z): 454.94 (Mnh), 7.3.663 5-fluoro-Mm4-I3-02- Similar to the preparation of IR4-|3-( 2-hydroxyethylamino)phenyl|-2-13-P4-(2-hydroxyethylamino)phenyl|-m2-(3-0M- hydroxyethylamino)Ycarbonylmethyleneaminophenyl|-5-fluoro-2,4-pyrimidinediamine, 5-methylamino)carbonylmethyleneaminophenyl and fluorine -М4-(3-(2-hydroxyethylamino)phenyl-М2-(3-(М-1-2,4-pyrimidinidiamine (5950233) methylamino)carbonylmethyleneamino) enyl)|-2,4-pyrimidinediamine is obtained as a result of the reaction of M2-(carboxymethyleneaminophenyl)-5-fluoro-M4-13-(2-hydroxystylamino)phenyl|-2,4-pyrimidinediamine and methylamine. PH/MS: retention time: 14.93 min; purity: 92.99; MS (m/z): 426.27 (MIN. 7.3.664 5-fluoro-M4-13-0- Analogously to the preparation of Ma-/3-(2-hydroxyethylamino chrenyl|-M2-13-HPM-(2- hydroxyethylamino )phenyl|-142-E3-1PM-(2- hydroxyethylamino)|carboniamethyleneaminophenyl|-5-fluoro-2,4-pyrimidinediamine, 5 methylamino)stylaminocarbonylmethylene | fluoro-M4-|3-(2-hydroxyistlamino)phenip|1- m2-13-IM-(2-methylamino)stilamino with aminophenyl-2,4-pyrimidinediamine carbonylmethyleneaminophenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction (K950234) 1M2-(carboxymethyleneaminophenyl)-3-fluoro-M4-(3- (2-Hydroxyethylamino)phenyl-2,4-opyramidinediamine and M-methylethylenediamine LC/MS: retention time: 11.39 min Purity: 97.79 MS (m/z): 468.96 (MH). 7.3.665 2-I3-ГМ-(2-М- Analogous to the preparation of Ma-Г3-(2-hydroxyethylamino)phenyl-m2-Г3-PM4-(2- benzipamino)ethylamino|carbonylmethyl | hydroxyethylamino)|carbonylmethyleneaminophenyl |-5- fluoro-2,4-pyrimidinediamine, M2 (Te naminophenyl-5-fluoro-Ma4-|3-(2- (3-1H-(2-M-benzylamino)stilamino|carbonylmethyleneaminophenyl-5-fluoro- M4-13-( 22- tihydroxyethylamino)phenyz |-7,4-tihydroxyethylamino)phenyl)|-2,4-pyrimidinediamine is obtained as a result of the reaction Х2- pyrimidinediamine (KU50235) (carboxymethyleneaminophenia)-5-fluoro-M4-134(2-hydroxyethylamino)phenyl|- 2,4-(2) pyrimidinediamine and M-benzypethylenediamine. РХ/MS: retention time: 14.39 min; purity: 97395; MS (m/z): 545.01 (MK). che 7.3.666 5-fluoro-MA-13-(2- Similar to the preparation of M4-|3-(2-hydroxyethylamino)phenyl| M2-(3-1M-(2- hydroxyethylamino)phenyl|-42-1340ch- tihydroxyethylamino) |carbonylmethyleneaminophenyl|-5-fluoro-2,4-pyrimidinediamine, 5- se morpholino)carbonylmethyleneaminophenyl!. | fluoro-Ч4-|3-(2-hydroxystylamino)phenyl|-142-13-14- -2,4-pyrimidinediamine (K950236) morpholino)carbonylmethyleneaminophenylI-2,4-pyrimidinediamine is obtained as a result of the reaction M2-(carboxymethyleneaminophenyl)- 5-fluoro-Ma-(3-(2- hydroxyethylamino)phenyl|-2,4-pyrimidinediamine and morpholine. LC/MS: retention time: 15.24 min; purity: 94.06; MS (m/z): 482.40 (MNK). 7.3.667 М2-13-(3-М,М- Analogous to the preparation of М4-(3-(2-hylproxyethylamino)phenyl|-М2-13-1М-(2- dimethylaminopropyl)aminocarbonylmeth | hydroxyethylamino )|carbonylmethyleneaminophenyl|-5-fluoro-2,4-pyrimidindiamine, «lenaminophenyl|-5-fluoro-M4-I(3-(2- M2-(34(3-MM-limethylaminopropyl)aminocarbonylmethyleneaminophenyl)|-5- fluoro-Ма4- hydroxyethylamino)phenyl|-2,4- (3-(2-hydroxyethylamino)phenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction M2-(carboxymethyleneaminophenyl)-5-fluoro-IM4 in virimidinediamine (K950237) -13-(2- with hydroxyethylamino)phenyl)-2.4-pyrimidinediamine and MM-dimethylpropanediamine.

PH/MS: retention time: 13.33 min; purity: 91.45; MS (m/z): 497.47 (MN). . и » 7.3.668 М2-13-(Ч42,3- Similar to the preparation of М4-(3-(2-hydroxyethylamino)phenium|-М2-13-1М-(2-dihydroxypropyl)amino|carbonylmethylene | hydroxyethylamino)|carbonylmethyleneaminophenyl-5 -fluoro-2,4-pyrimidinediamine, amicophenyl-5-fluoro-YH4-(3402- M2-13-1M-(2,3-dihydroxypropyl)amino|carbonylmethyleneaminophenia)-5-fluoro-M4-13-hydroxystylamino)phenyl| -2,4- (2-tihydroxyethylamino)phenyl-2,4-pyrimidinediamine is obtained as a result of the reaction pyrimidinediamine (K950238) M2-carboxymethylaminophenyl)-5-fluoro-m4-|3-(2-hydroxyethylamino)phenyl|-2,4 - (ee) pyrimidinediamine and 1-amino-2,3-propanediol. LC/MS: retention time: 12.86 min; purity: 90.099; MC (m/z): 486.40 (MN). io) 7.38.669 5-fluoro-M4-|3-(2- Similar to the preparation of M4-|3-(2-hydroxyethylamino)phenyl|-M2-|3-1M42- hydroxyethylamino)phenyl|-Mm2-|3-0M - hydroxyethylamino)|carbonylmethyleneaminophenyl-5-fluoro-2,4-pyrimidinediamine, 5 shko morpholinoethyleneamino)carbonylmethyle | fluoro-MA-13-(2-tihydroxystylamino)phenyl)-IM2-|34/M-naminophenyl)|-2,2-pyrimidinediamine morpholinoethyleneamino)carbonylmethyleneaminophenyl|-2,4-pyrimidinediamine "se 20 (8950239) is obtained as a result of the reaction M2-(carboxymethyleneaminophenyl)-5-fluoro-Ma-13-(2- (42)

F) ko 60 b5 of hydroxystilamino)phenyl|-2,1-pyrimidinediamine and 4-4(2-aminosyl)morpholine. РХ/МС: retention time: 13.52 min; purity: 92.49; MS (m/z); 525.47 (MENU). 7.3.670 2A-bisoxy-mehylic ether of tyrosine|- Mixture of methyl ester of tyrosine (58 mg, 0.3 mmol), 2.4-diphor-5-5-stoxycarbonylpyrimiline (2926514) ethoxycarbonylpyrimidine (44 mg, 0.1 mmol) in MeOH (2 ml) is heated in a hermetically closed flask at a temperature of 100 °C overnight, dissolved in water (20 min), acidified with M NOI and extracted with ethyl acetate (3 x 25 ml).

3-Ethoxycarbonyl-2-methoxy-4-(M-) The solvent is evaporated, and the residue is purified by preparative TLC using H-tyrosine methyl ether|pErymidine 3095 EMO Ashexanes to obtain a mixture of 2,4-bis ) of tyrosine |-5-ethoxycarbonylpyrimidine (5926514). 1H NMR (SOSIS): I B.bOKIN, 1: 6.6 Hn), 8.36 (in, 1H), 7.05a, 2H, 1- 8.7 Hz), 6.84 (4, 2H, 1-1 Gy), 6.74 (y, 2H, 1-2 9 Hz), 6.54 (d, 2H, 1-9 Hz), 4.82 ( i, 2А, 12: 6 Gy), 4.25 (d, 2Н, 2- 6.3 Hz), 3.73 (в, ЗН), 3.72 (5, ЗН), 3.06 (t, 48) . 5, 1H), 8.65 (0, IN, 1st 6.9 Hz), 7.02 (ai, 2H, 1-21 and 6.3 Hz), 6.77 (49, 2H, )- 2.4 and 6.6

Gi), 4.93 (4, 1H, 1- 1.5 and 6.9 Go), 4.30 (9, 2H, 1: 8.1 Hyd), 3.90 (in, ЗН), 3, 70 (5, ЗН), 3.17 (49, IN, 1- 5.4 Hz), 3.06 (44, 1Н, 3 7.5 and 7.8 Hz), 1.33 (1, ЗН, 1- 6.9 Hyd),

PH/MS: retention time: 22.58 min; purity: 9995; MS (m/zu: 376 (M Kk). 7.3.571 M2,m4-bis(3,4-ethylenedioxyphenyl)-5- Analogously to the preparation of M2,M4-bis (H-methyl ester of I.-tyrosine|-5- ethoxycarbonium-2,4-pyrimidinedigmine of ethoxycarbonylpyrimidine, M2,144-bio(3,4 ethylenedioxyphenyl)-5-thoxycarbonium- (89262572) 2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-ethoxycarbonylpyrimidine and 3,4 -ethylenedioxyanipin. IN NMR (OM5O-y6UK 10.01 е5, 1Н), 9.65 (н5, IN), 8.62 (5, NO), 7.18 (5, 2Н), 7.04 (yes, 1H, 12: 1.8 and 8.7 Hz), 6.93 (4, 1H, 7: 7.5 Hz), 6.76 (0, IN, 1: 8.7 Hz), 6.654, IN, )- 8.7 Hz), 4.28 (4, 2H, 1 6.9 Hz), 1.31 s ZN, 2 7.2 Gy); LC/MS: retention time: 27.25 min; purity: 10095; MS (m/z): 451 (MIN). 7.3,672 M2/M4-bis(4- Similar to the preparation of M2,M4-bis|M-methyl ether of I.-tyrosine|-5-methoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonylpyrimidine, M2,44-bis(4-methoxycarbonylmethyleneoxyphenyl-5- ethoxycarbonyl-2,4-pyrimidinediamine ethoxycarbonyl-2,4-pyrimidinediamine (8926253) is obtained as a result of the reaction of 2,4- (К926253) dichloro-5-stoxycarbonylpyrimidine and ethyl 4-aminophenoxyacetate. IN NMR (СБ3О:О 8.60 (65 . 2NU, 4.44 (a, 2H, 7: 6.9 Hz), 3.79 (5, ZNO), 1.40 (i, ZN, 7- 6.9 Gy); RY/MS: duration of retention: 25 ,83 min; purity: 8995; MS (m/z): 5 (MH). 7.3.673 2,4-bis|M-ethyl ether Analogous to the preparation of M2,Ch4-bis|M-methyl ether of I.-tyrosine| -5-si phenylalanine|.5- ethoxycarbonylpyrimidine, 2,4-bis|M-ethyl ether of I.-phenylalanine |-5- ethoxycarbonylpyrimidine (K926525) ethoxycarbonylpyrimidine is obtained as a result of the reaction of 7,2-dichloro-5- o ethoxycarbonylrimyshine and ethyl ether ethyl 1.-phenylapanin y MeOB or

KEOAs. IN NMR (SOSIZU OO 8.55 (6, 1H, 17.2 Si), 8.51 (5, 1H), 7.35-7.10 (t, 108), 5.88 (4, 1H, 2 -22 6 Hz), 4.88 (440, 1H, and: 6.3 Gy), 4.80 (490, 1H, 3- 5.3 Gy), 4.23 (9, zn, 1- 72 Co ), 12 (9, YAN, 7- 7.2 Go), 3.65 (1, 2H, 22 6 Hz), 3.56 (6 24, 4-60 GI), se 1.30 4, 2H, , 22 6 ih), 1.30 0, ZA, 722 7.9 Hz), 1.20 (t, 6H); LC/MS: retention time: 32.22 min; purity: 8995; MS (m/z): 535 (MNYU). Ф 7.3.674 2,4-bism-ethyl ether of 1-valinyl|-5- | Analogous to the preparation of Mo, m4-bis| M-methyl ester of I-tyrosine|-5-ethoxycarbonylpyrimidinium (K926527) of ethoxycarbonylpyrimidine, 2,4-bis! M-ethyl ether of 1.-valinyl|-5-"- ethoxycarbonylpyrimidine is obtained as a result of the reaction of 2,4-dichloro-5- ethoxycarbonylpyrimidine with ethyl ether of 1"-valine in MEON or ЕХ6ХАs.

IN NMR (SOSIZ): O 8.59 (d, 1H, 1- 7.8 Ga), 8.56 (5, 1H), 5.69 (4, IN, 1: 8.7 Hz), 4, 62 s (t, IN), 4.51 (t, 1H), 4.25 (d, 2H, 12 7.5 Gy), 4.20 (t, 4), 2.20 (t, 2H), 1.34 (i, ZN,

ZB 1-7.8 Hn), 1.27 (6 BN, 1: 7.5 Hz), 1.00 (p, 12H); РХ/MS: retention duration: (ee) 29.27 sq; purity: 9795; MS (m/z): 439 (MN). 7.3,675 5-ethoxycarbonyl-M2-(3Z-tihydroxyphenyl)- | As a result of the reaction of 2-chloro-M4-(3-hydroxyphenyl)-5-ethoxycarbonylpyrimylinamine 4-1M-ethyl ether of 1.-phenylalanine |-2- with 3 equivalents of M-ethyl ether of I.-phenylalanine in methanol at the temperature of pyrimidine (5926528 ) 80-100 oC for 24 hours, followed by dissolution with water and acidification with 2M NOSI, an acidic solution is formed. The obtained solution is extracted with EU As, and the precipitate is purified by column chromatography on silica gel, obtaining 4-|M-ethyl ether of 1-phenylalanine|-M2-(3-tihydroxyphenyl)-5-ethoxycarbonyl-2» shch pyrimidineamine. IN NMR (SOSIZ): Gy 94 (5, NU, 9.13 (а, 1, 1-6 Hz), 8.45 55, с 18), 7.59 (5, 1Н), 7.34-7 ... 1.8 and 7.8 Hz), 4.86 (di, 1H, 3Z and 5.1 Gy)u, 4.32 (a, 2H, 126.3 Gy), h z» 4.19 (a 2H, 72: 7.2 Gihu, 3.30 (44, 1A, 1: 4.8 and 8.7 Gu, 3.18 (99, IN, 15 5.1 and 8.7 Hz), k 1 ,36 0, ZN, 7- 6.9 Hz), 1.65 (, ZN, 1- 7.2 Hz); LC/MS:; retention time: 27.49 min; purity: 9125; MS (m/ z); 451 (МН к). 7.3.676 M2-(3,4-ethylenedioxyphenyl)-5- Analogously to the preparation of 4-HYM-stylyl ether of I. phenylalanine) M24(3-ethoxycarbonyl-4-|M-stylyl ether 1 - hydroxyphenyl)-3-ethoxycarbonyl-2-pyrimidinamine, ИМ2-(3,4-ethylenedioxyphenia)-5-(ог)phenylglycine)-2-pyrimidinamine ethoxycarbonyl-4-|M-ethyl ether of I-phenylelicine|-2-pyrimidinamine obtained in (K926536) as a result of the reaction of 2-chloro-5-ethoxycarbonyl-4-|YH-ethyl ether I.

KkZz phenylglycine)pyrimidine with 3,4-ethylenelioxyaniline in MEON or EYU As. 1 NMR (SOSIZuM 9.15 (5, 1H), 8.9 (5, IN), 8.61 (5, 1), 7.48 (t, 2H), 7.38 (t, Z), 7 .16 (56, - 1), 6.80 (t, 2HO, 5.75 (4, 18), 4.24 St, 6H), 3.66 (5, ZNU, 1.35 (6 ZN); HPLC: retention time: 28.16 min; purity: 8592: MS (m/z): 465 (MH). (Te) 20 Analogous to the preparation of 4-H-ethyl ether of 1--phenylalanine)-M2-(3- ( 42)

Ф) ko 60 b5 butoxycarbonylmethyleneoxyphenyl)-5-hydroxyphenyl)-5-ethoxycarbonyl-2-pyrimidinamine, M4-(4-tertoxycarbonyl-M2-(4-butoxycarbonylmethyleneoxypheny)-5-ethoxycarbonyl-yХ2-(4- methoxycarbonylmethyleneoxyphenyl)- 2,4-|Methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine is obtained as a result of pyrimidinediamine (8926579) reaction of M4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-2-chloro-5-ethoxycarbonyl-4-pyrimidinamine and methyl 4-aminophenoxyapatate. IN NMR (SOSIZ): At 10.17 (5,

IN), 8.73 (5, IN), 8.45 (v5, МН), 7.49 (4, 2Н, 12 877 Hz), 7.43 (4, 2Н, 12 8.7 Hz), 7 .33 (5, IN), 6.87 (0, 2H, 1-6 Hz), 6.84 (d, 7, 1: 5.7 Hz), 4.63 (5, 2H), 4.53 (5, 2H)), 4.33 (9, 2H, 7- 6.9 Hz), 3.81 (in, ZNI), 1.49 (5, 95), 1.39 (i, ZN, 3 : 7.5 Hn); PH/MS: duration of retention: 27.93 min; purity: 9692; MS (m/z): 553 "(MIN). M4-(4-tert) - (4-methoxycarbonylmethyleneoxyphenia)-5-|butoxycarbonylmethyleneoxyphenyl5-methoxycarbonyl-M2-(4-70 methoxycarbonyl-2,4-pyrimidinediamine methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine is obtained as a result of (8926580) reaction M4-(4-tert-butoxycarbonylmethyleneoxyphenyl) )-2-chloro-5-stoxycarbonyl-4-pyrimidinamine with methyl 4-aminophenoxyacetate. The 5-methyl ether is obtained as a result of the cross-esterification reaction in MEOH. 1H NMR (SOSISU: 7 16.13 (5,

IN), 8.73 (5, IN), 8.45 (05, 1H), 7.49 (0, 2H, 1- 8.7 Go), 7.43 (4, 2H, 3-2 8, 7 Hz), 7.33 (B5, IN), 6.87 (t, 4), 4.63 (5, 2H)), 4.53 (5, 2H)), 4.33 (4, 2H, 1- 6.9 Gy), 3.88 (5, ЗН)), 3.81 «8, ЗН), 1.49 (5, 9Н), РХ/MS: retention time: 27.43 min; purity: 10095;

MS (m/z): 539 (MN). 7.3.679 Ma-(4-carboxymethyleneoxyphenyl)-5- As a result of processing M4-(4-tert-butoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-M2-(4-ethoxycarbonyl-M2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine methoxycarbonylethyleneoxyphenyl)-2,4- | with trifluoroacetic acid in TNE:H2O at room temperature, M4-pyrimidinediamine (KU25583) (4-carboxymethyleneoxyphenyl)-5-ethoxycarbonyl-M2-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine is obtained. IN NMR (0М50-46Х SI 10.03 (5, IN), 8.65 (5, 1Н)), 7.49 (Ba, 4Н. 1- 8.7 Gy), 6.89 (8, 2Н, 12: 953 Gi), 6.81 (0, ?2H, 1-8 Go), 4.70 (5, 2H), 4.65 (5, 2NI), 4.33 (4, 2H, 1: 6.9 Gi), 3.81 (5, ZN), 1.49 (5,

ОН), 1.39 (i, ЗН, 1-7.5 Ha); LC/MS: retention time: 22.28 min; purity: 7390;

MS (m/z): 497 (MN.Yu). 7.3.680 M244-carboxymethyleneoxyphenyl)-5- As a result of processing M2-(4-tert-butoxycarbonylmethyleneoxyphenyl)-5-ethoxycarbonyl-M4-(4.ethoxycarbonyl-mi-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine methoxycarbonylmethyleneoxypheny). 2.4-| with trifluoroacetic acid in TNE:H2O at room temperature, M2-pyrimidinediamine (K926584) (d4-carboxymethyleneoxyphenyl)-5-euthoxycarbonyl-MA-(4-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinedigmine is obtained. 1Н NMR (0М5О-46к ГИ 19.01 (5, 1), 8.64 (5, 18), 7.45 (fa, 4Н, 3-7.2 Г), 6.904, 2Н, 1-2 8, 7 Hz), 6.75 (d, s 2H, 3- 8.4 Gy), 4.80 (5, 2), 4.38 (5, 2H), 4.26 (da, 2H, 1- 7.2 Gi), 3.79 (5, ZNI), 1.30 (. (5)

ZN, 1-2 7.2 Hz); РХ/МС: duration of retention; 22.37 minutes; purity: 10099; MS (m/z): 497 (MN). 7.3 581 5-carboxy-M2-(3-hydroxyphenyl)-M4-(M- | As a result of hydrolysis of M2-(3-hydroxyphenia)-5-ethoxycarbonyl-4-(M-ethyl ether (1)-pheniaglycine)-2 5-carboxy-M2- (K926535) (3-tihydroxyphenyl)-M4-HP4-(1)-phenyllysine)-2-pyrimidynamin. IN NMR (SOZO0HO is e) 8.89 (5, IN), 8.50 (5, 180), 7.43 (t, 2NI), 7.33 (pi, ZN), 7.14 (t, 2H )), 6.98 (t, 2NI), 6.62

Cht, 1H), 5.71 (5, IN RF/MS: retention time: 17.75 min; purity: 7390; MS (e") (m/zu: 382 (MN. 7.3.682 5-amino-6 -ethoxycarbonyl-M2,M4-bis(3- Prepare a suspension of b-ethoxycarbonyl-M2,M4-bis(3-hydroxyphenyl)-5-nitro-2,4-che tihydroxyphenia)-2,4-ptrymidinediamine pgrymidinediamine and 1095 РО/С ( 1095 by weight) in ethanol and carry out its reaction in a Parr bottle (K925855) in an atmosphere of hydrogen gas (under a pressure of 1.4 atm) for 1 sem hour. The reaction mixture is filtered through celite. As a result of purification by column chromatography, 5-amino-6 -ethoxycarbonyl-M2M4-bis(3-c thydroxyphenyl)-2,4-pyrimidinediamine, IN NMR (SOSO): SI 7.30 (vv, 1), 7.18-7.10 (t, ZN), 7, 00 (6 2H, 1-8.1 Hyd), 6.59-6.54 (t, 1H), 6.33 (44, 1H, 1-21 and 11.1 Go), 4.39 (4, 2H, 1-5 6.9 Hz), 1.43 (i, ЗН, 1» 6.9 Hn); EX/MS; retention time: 19.24 min; purity: 19095; MS (m/z): 382 (MN). 7.3.683 5-amino-5-ethoxycarbonyl-M2,M4-bis(3,4- ethylenedioxyphenyl)-2,4-pyrimidinediamine | 2.4-pyrimidinediamine, 5 amino-b-ethoxycarbonyl 1M2,M4-bis(3,4-ethylenedioxyphenyl)" (K925857) 2,4-pyrimidinediamine is obtained as a result of the reaction of b-ethoxycarbonyl-M2,M4-bis (3,4 -ethylenedioxyphenyl)-5-nitro-2,4-pyrimidivdiamine, hydrogen, and 1095 ROS. 1H - s NMR (SRZOUIO 7.16 (y, IN, 2 2.4 Gy), 7.07 (y, IN, 2 2.4 Hz), 7044, 1H, I 2.4 and 9.0 Gy) , 6.84-6.79 (t, 2H), 6.70 (y, IN, 1- 9.0), 4.43 (a, 2H, 1- 7.8 Hz), 4.25 (5 , n «H), 4.21 (B5, 4H), 1.43 (b 3H, 3-7.8 Gy); PH/MS: retention time: 23.70 min; purity: 10095; MS (m/z): 466 (MH). 7.3.684 5-amino-M2,ma- Similar to the preparation of 5-amino-6-ethoxycarbonyl-M2,m4-bis (3-hydroxyphenyl) - bis(hthoxycarbonylmethyl)-b-2,A-pyrimidinediamine, 5 amino-M2,M4-bis(ethoxycarbonylmethyl)-b-ethoxycarbonyl-ethoxycarbonyl-2,4-pyrimidinediamine 2,4-pyrimidinediamine is obtained as a result of the reaction of b-ethoxycarbonyl- ИМ2,М4-о (8925865) bis(ethoxycarbonylethyl)-3-nitro-2,4-pyrvmidinediamine, hydrogen, and and 095 ROW/S. 1Н

NMR (SOSISU GI 6.25 (65, 2H), 4.38 (a, 2H, 22 6.9 Hz), 4.23-4.14 (t, 6NI), 4.05 (65, 2NU, 1 .39 (6 ZA, 2-69 Gy), 1.30-1.22 (t, 6H); RH/MS: retention time: 17.67 io) min; purity: 9595; MS (m/13: 370 (MH). - 5-amivo-M2,Ma-bis(4- As a result of hydrogenation of 2, M4-bis(4-stoxycarbonylmethyleneoxyphenia)-6-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-nitro-2,4-pyrimidinediamine from 5-amino-M2,IM4-bis(4-stoxycarbonylmethyleneoxyphenyl)-42) ko 60 b5 is obtained by using Ra/C in MeOH under 50% ethoxycarbonium-2,4-pyrimidinediiumMn at a pressure of 2.7 atm

(K926567) b-ethoxycarbonyl-2,4-pyrimidinediamine, 1H NMR (SOSIZKO 7.47 (0, 2H, I 8.7 Gy), 7.A1 (9, 2H, 1-8.7 Hz), 6, 88 (a, H, 2- 8.1 Hz), 6.81 (y, 2H, 2- 8.7 Gy), 4.63 (5, 28), 4.59 (5, 2H), 4, 41 (4, 2H, 2-:7.5 G i), 4.29 (t, 4), 1.44 (i, ZNI), 1.31 (t, 68); RHU/MS: duration of retention: 26.15 min; purity: 9795, MS (m/z); 554 MN), 7.3.686 M2,M4-bis(4- In a dry vessel, which is equipped with a rubber membrane and a tube for feeding M2, 9 ethoxycarbonylmethyleneoxyphenyl)-6 - fill with 5-amino-M2,M4-bisg4-ethoxycarbonylimstylenoxyphenyl)-6-ethoxycarbonyl-5-ethoxycarbonyl-2,4-pyrimidinediamine, an equimolar amount of pyridine and (phenylaminocarbonylamino)-2,4-phenylisocysnate at room temperature. The resection mixture is diluted with pyrimidinedismine (KU26571) overnight at room temperature, 2 the resulting mixture is passed through n-hexane to precipitate the desired product M2,M4-b1c(4-ethoxycarbonylmethyleneoxyphenyl)-b-stoxycarbonyl-5-(phenylaminocarbonylamino)-2,A- pyrimidinediamine. YIN YAM? (SOSIZUO 7.92 (5, 1H), 7.47 (z, 18), 7.35 (B 5H, 1- 8.4 Go), 7.25 (B IN, 3 7.5 Gy), 7.03 (t, 2H), 6.81 (4, ZN, 1-2: 8.7 Hz), 6.76 (4, 2H,I- 8.7 Hz), 4.60 (in, 2NU, 4, 58 (5, 2Н), 4.29 (t, 6Н), 1.45 (t, 9Н); LC/MS; retention time: 27.75 min; purity: 9190; MS (m/z): 673 ( 7.3.687 5-allylaminocarbonylamino-M2,M4-bis(4- | Similar to the preparation of M2,M4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-stoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4 -pyrimidinediamine, 5-ethoxycarbonyl)-2,4-pyrimidinediamine allylaminocarbonylamino-im2,M4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6- (5926585) ethoxycarbonyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-amino-

M2,MA-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,4-pyrimidinediamine with allyl isoacetate. LC/MS: retention time: 25.60 min; purity: 9195; MS (m/z): 637 IMN). 7.3.688 42,M4-bis(4- Similar to the preparation of M2,M4-bis(4-stoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine, 142, 44-6is (4-ethoxycarbonyl-5-ethoxycarbonylmethyleneoxyphenyl)-b-ethoxycarbonyl-5-(ethoxycarbonylaminocarbonylamino)- (ethoxycarbonylaminocarbonylamino)-2,4-pyrimidinediamine is obtained as a result of 2.4-5-pyrimidinetriamine (8926586) reaction of 5-amino-M2,M4- bis (4-ethoxycarbonylmethyleneoxyphenyl)-b-ethoxycarbonyl-2,4-pyrimidinediamine and ethoxycarbonyl isocyanate... LC/MS: retention time: 26.79 min; purity: 8892; MS (m/z): 669 (MN). 7.3.689 M2,M4.-bis(4- Similar to the preparation of M2,M4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylamisocarbonylamino)-2,4-pyrimidinediamine, M2,M4- bis(4-ethoxycarbonyl-5-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycaronyl-5- (epoxycarbonylmethyleneaminocarbonyl (ethoxycarbonylmethyleneaminocarbonylamino)-2,4-pyrimidinediamine is obtained in Gamino)-2,4-pyrimidinediamine (K926587) as a result of the reaction of 5-amino-M2,M4- bis(4-ethoxycarbonylmethyleneoxyphenyl)-b-

Ethoxycarbonyl-2,4-pyrimidine diamic acid with ethyl acetonyl isocyanate. РХ/MS: he) nin duration of retention: 25.76 min; purity: 9670; MS (m/z): 683 (MN). 7.3.690 Mm2,Mma-bis4- Analogously to the preparation of M2,M4-bis(4-ethoxycarbonylmethyleneoxyphenyl)-b-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(phenylaminocarbonylamino)-2,4-pyrimidinediamine, M2,M4-bis(4 - stooxycarbonyl-5-ethoxycarbonylmethyleneoxyphenyl)-b-estoxycarbonyl-5-(cyclopentylaminocarbonylamino)-2,4-(cyclopentylaminocarbonylamino)-2,4-pyrimidinediamine is obtained as a result of (Ce)pyrvmidinediamine (K926588) reaction of 5-amino-M2,M4- bis(4-ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-2,A4-pyrimidinedimix with cyclopentyl isocyanate. РХ/MS: retention time b: 27.36 min; purity: 8396; MS (m/z): 665 (MIN Kk). 7.3. 691 M2,Ma-vis(4- Analogous to the preparation of M2,M4-bis(ethoxycarbonylmethyleneoxyphenyl)-6- or!ethoxycarbonylmethyleneoxyphenyl)-6-ethoxycarbonyl-5-(M-phenylformyl-amino)-2,4-pyrimidinediamine, M2,M4 -bis(4-ethoxycarbonyl-5-ethoxycarbonylmethyleneoxyphenyl)-b-ethoxycarbonyl-5-ure (chloroacetylaminocarbonylamino)-2,4-(Chloroacetylaminocarbonylamino)-2,4-pyrimidinedimine is obtained as a result of pyrimidinediamine (K926589) reaction M5-amino-M2, m4-bis(ethoxycarbonylmethyleneoxyphenyl)-b-ethoxycarbonyl-

From 2.4-pyrimidinediamine with chloroacetylformyl isoacetate. LC/MS: duration (he) of retention: 26.60 min; purity: 100995; MS (m/z): 580 (MN). 7.3.692 (8920669): M2, Ma-bis(3,4- Mixture of 2,4-dichloro-5-trifluoromethylpyrimidine (416 mg, 1.9 mmol), 3,4- ethylenedioxyphenyl)-5-trifluoro-2, 4- ethylenedioxyaniline (0.5 ml, 4.1 mmol), and concentrated NCI. (0.1 ml) in 1: 9 pyridinediamine acetone/H?2O (10 ml) is heated in a flask with a reflux condenser. By ! hour, the reaction is completed, as determined by the TIIH method. Sumi) "cool down to room temperature and overcome EKO As (30 ml). The organic layer is washed with 2 M HCl (2 x 15 ml), water (15 ml), and dried (Ma?2504). shsh

The organic layer is filtered through silica gel, and the filter residue is washed with ECHO Ac and evaporated. The obtained material is purified by chromatography (silica gel, 95; 5 dichloromethane/ethyl acetate), obtaining M2,Ma4- h z» bis(3 a-styrenedioxyphenyl)-5 -trifluoro-2,4-pyridinediamine (380 mg, 4495): CC0.27 " (silica gel, 9.5: 0.5 dichloromethane/ethyl acetate); mp 141-143 C; 1? NMR ("300 MGy,

SOSIZ) 5 8.25 (5, 1H), 7.07 (t, 2H), 6.99 (f5, 18), 6.93-6.84 (t, ЗН), 6.77-6.74 (t, 1H), 6.67 (5, 1H), 2.29-4.24 (t, 8H); 13 C NMR (75 MGy, SOSIZ) 8 161.2:157.9; 155.8; 143.75 132.65131.1:117.55 417.35 114.4; 113.2; 110.3; 64.7; 64.5; IR (NPIVV))

Go | 3446 of Art.); TEZ MS pu 447 |С21НИ7Р3М404 4 NIK; VERH (Method C) 29995 (AS), 18. -8.5 min. Similarly, calculations are made for С21Н17ЕЗМ4ОА: С, t 56.50; H, 3.84; M, 12.55. Found: C, 56.46; N, 4.41; M, 12.57. 7.3.693 (8920668): M4-(3,4-ethylenedioxyphenyl)- | A mixture of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine (280 mg, - 5-fluoro-im2-(3-pyridinium)-2,4-mmol), 3-aminopyridine ( 113 mg, 1.2 mmol), sodium II-butylate (134 mg, 14 pyrimilindiamine mmol), binapu (38 mg, 0.06 mmol), and palladium (its) zeatate (14 mg, 0.06 mmol) in 9 nitiiizhnvlzhtzhzhlyn? lLIIIUSHTSHNNYNYITTIININNY (Se) 42) to 60 b5 ml of toluene is purified from M2 (3 cycles of alternate supply of MO and vacuum).

The mixture is heated to 80 o C (oil bath temperature). After 24 hours, the mixture was cooled to room temperature and EIOAc (30 mL) and water (10 mL) were added. After stirring for 15 minutes, the precipitate is collected by filtration. The composition of the solid substance (150 mg) is determined with the help of 19 NM ha ionization mass spectra by electrospinning (TICH analysis of the organic layer of the filtrate revealed only the starting materials). The raw product is mixed to a paste-like consistency in 2 M HCl, the mixture is filtered. The filtrate is neutralized with 1095% aqueous solution of MaOH and evaporated. The obtained material is mixed with MeOH to a paste-like consistency, and the solid substance is filtered off. The evaporated substance is stirred to a paste-like consistency in SNHSM, and TEA (trifluoroacetic acid) is added, obtaining a solution. MM-diisopropylethylamine is added to this solution, the solid substance is collected by filtration, washed with SNZIST, and then E(200, obtaining

M4-(3,4-Stylenedioxyphenyl)-5-fluoro-M2-(3-pyridyl)-2,4-pyrimidinediamine (55 mg, 1496): KE 0.42 (silica gel, 4:1:0.1:0 ,1 dichloromethane/ethyl acetate/ methanode/concentrated ammonium hydroxide); tr 2515 25322. IN NMR (300 MGl, OM5O-y6) 5 9.38 (5, IN), 9.26 (in, NN), 8.74 (5, 18), 8.20- 8.17 ( t, 1), 8.09-8.08 (t, 2, 7.29-7.28 (po, 190), 723-717 (t, 2H), 5.83-6.80 (t, 1NU . ; 137.55132.1; 124.8; 123.0; 116.45 115.1; 110.9; 64.1; 64.05 IC (NPVV) 3264, 3195 st-1; KhTAD MS pu 340 (С17Н14ЕМ505 4- NO. Similarly calculated for СИ7НИЯ4ЕМ50О2:0.5Н20: C, 58.70; H, 4.20; M, 20.13.

Found: C, 58.71; H, 4.20; M, 19.51. 7.3.694 (5920664): M443,4-ethylenedioxyphenyl)- | To a solution of 2-chloro-IM4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimilinamine (0.25 g, 5-fluoro-M2-14-n-hexyloxyphenyl)-2,4- 0.89 mmol ), which is stirred magnetically in styrene glycol (3.0 ml) in a pyrimidinediamine nitrogen atmosphere at room temperature, add MM diisopropylethylamine (0.12 g, 0.89 mmol), and then 4-hexyloxyaniline (0.27 g, 1.4 mmol). The reaction mixture was heated to 170°C for 5.5 hours, then cooled to room temperature and partitioned between water (20 mL) and chloroform (20 mL). The aqueous layer was extracted with chloroform (20 ml), the mixture of organic layers was dried (Ma?2504), filtered and evaporated in vacuo. The resulting crude brown solid is purified by chromatography (Snlica gel, 2:1 hexanes/ethyl acetate) to give M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(4-n-texyloxyphenyl)-?,4-pyrimidinediamine ( 0.09 g, 2399) in the form of a white solid phase: KHO,53 i. (silica gel, 4: | chloroform/ethyl acetate); street 115-1172 S; 1 H NAM (500 MHz, ----- plo o SOSIZ3) 7.90 (6. 153.2 Gy 1H), 7.40 (0. 158.9 Hz, 2H), 7.29 (0. 3- 2.5 Hu, 2H), 698, i) 1-8.8 gy, 1), 6.88-6.82 (t, ZN), 6.61 (5. 1), 4.29 (4, With Hz, 4H), 3.94 s, 16.6, 6.7 Hz, 2H), 1.77 (t, 2H), 1.47 (t, 2H), 1.35 (t, 4H), 0.92 (pi, ZN); IZS NMR (75

MHz, SOSI3) 156.3, 155.1, 150.3, 143.6, 142.7, 140.3, 140.07 139.4, 133.0, 131.7, 121.9, 117.3, 115.0 , 114.7, 110.8, 58.6, 64.6, 31.8, 29.5, 25.9, 22.8, 14.2; IC (Che) zo (NPVV) 3357 sty-1; TEZ MS powder 439 |(C24H27EM403 i NIk; HPLC (Method B) 98.55 (AOS), -7.9 min. Similarly calculated for C24H27EM403: C, 65.74; F

H, 5.21; M, 12.78, Found: C, 65.34; H, 6.19; M, 12.95. 7.3.695 (K920666): M2-(4-p-butyloxyphenyl)-M4- | To a solution of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine (0.25 g, che 43,4-ethylenelioxyphenyl)-5-fluoro-2,4- 0.89 mmol) , which is magnetically stirred in ethylene glycol (3.0 ml) in a pyridinediamine nitrogen atmosphere at room temperature, add 1M diisopropylethylamine (0.12 g, 0.89 mmol), and then 4-butoxyaniline (0.18 g, 1 .1 mmol). The reaction mixture and. heated to 185°C for 5 hours, then cooled to room temperature and partitioned between water (20 mL) and ethyl acetate (20 mL). The aqueous (ee) layer was extracted with ethyl acetate (20 mL), and the mixture of organic layers was dried (Ma2504), filtered and evaporated in vacuo. The resulting crude brown solid is purified by chromatography (silica gel, 2; 1 hexanes/ethyl acetate) to give M2-(4-p-butyloxyphenyl)-M443,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyridinediamine (0.18 g, 4990) in the form of a yellowish-brown solid phase: CI 0.66 (silica gel, 4: 1 chloroform/stilacetate); street 133-1352 S; EN NMR (300 MGy, SOSIZ) 5 7.89 (0, 1-3.2 Ha, 15, 7.39 (8, 128.9

Hz, 2H), 7.28 (4, 122.5 Hz, 18), 6.95 (460, 328.7, 2.5 Hz, 1H) 6.90-6.81 (t, 4H), 5.60 - s (0.1-2.4 Hz, 1), 4.27 (5, 4H), 3.94 (1, 126.5 Hz, 2NU, 1.80-1.71 (t, 2), 1, 55-1.42 (t, 2NU, 0.97 (64-73 Hn, ZNU; IZ C NMR (75 MG, SOSIZ)6 156.3; 155.1; 150.4; 143.6; h 142, 7; 140.3; 140.0; 139.4; 133.05 131.7; 121.9:117.3:115.0; 114.7; 110.8; 68.2; 64.7; a 64.5; 31.6; 19.4; 14.0; IR (NPVV) 3356 st-1; IEZ MS pu/t 411 Y C22NOZEM403 4 H 15: HPLC (Method C) 29995 (ASHS), (B - 17.3 min. Similarly calculated for C22H2ZEM4O3: C, 64.38; H, 5.65; M, 13.65. Found: C, 62.64; H, 5.59; M, 13.15.

Go! 7.3.696 (K920670): M4-(4-ethyloxyphenyl)-2- To a solution of 2-chloro-4-(3,5-ethyloxyphenyl)-5-fluoro-4-pyrimidinamine (0.25 g, 0.93 ( 3,4-ethylenedioxyphenyl)-5-fluoro-2,4-mmol) in ethylene glycol (3.0 ml) in a nitrogen atmosphere at room temperature, add pyrimidinediamine and -PI2ECM, (0.93 mmol), and then C,4- ethylenedioxyaniline (0.17 g, 1.12 co mmol). The reaction mixture is heated to 200 oC for 5 hours, then cooled to room temperature. The mixture was partitioned between H2O (20 ml) and 20 mL of EtOAc (20 mL), the aqueous layer was extracted with BIO-Ac (20 mL). The mixture of organic layers is dried (Ma2504), filtered and evaporated in vacuo. The obtained raw "20 brown solid substance is purified by chromatography (2:1 SNCI3/KU As), 42) (F, ko 60 b5, obtaining M4-(4-ethyloxyphenyl)-M2-(3,4-ethylenedioxyphenia)-z- fluoro-7,4-pyrimidinediamine (0.21 g, 6095) in the form of a solid phase of yellowish-brown color: КИ 0.42 ( 4:1 СНСИЗ / ЮА ес ); tr 163.8-167.29 С (Ю5С) ; 1H NMR (300

MHz, SOSIZ)5 7.89 (0, 222.8 Hz, 1H), 7.50-7.45 (t, 2H), 7.17 (4.2-2.5 Hz, 1H)), 6 ,02- 6.86 (t, ZN), 6.80-6.75 (t, 2NU, 6.64 (b5, IN), 4.26-4.21 (t, 4H), 4.03 ( 4, 2-7.0, 28), 1.42 0 7-6.9 Hz, ZN); 136 YAM (75 MGy, SOSIZU 156.1, 150.6, 143.6, 142.8, 140.3, 140.0, 139.5, 139.3, 134.0, 130.8, 123.2, 117.2 . ) 98.195 (AOS) "V. 12.0 min. Similarly calculated for С2ЛИН1ИЗЕМАОЗ:

P. 62,82; N, 5.01; M, 14.65. They reveal: C, 62.06; N, 5.01; M, 14.35. 7.3.597 (K920671): M4-(4-in-butyloxyphenyl)-M2- | Similar to the preparation of M4-(4-ethyloxypheny)-M2-(3,4-ethylenedioxyphenyl)-5-

OZ of A-styrenedioxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine, M4-(4-p-butyloxyphenyl)-M2-(3,4-ethylenedioxyphenyl)-pyridinliamine 5-fhor-2,4 -pyridinliamine is obtained as a result of the reaction of 2-chloro-M4-(4-p-butyloxyphenyl)-5-fluoro-4-pyrimidinamine with 3,4-ethylenedioxyaniline. The crude product is purified by chromatography (2: 1 SNSIZ/EO As); (0.17 g, 5295) In the form of a yellowish-brown solid phase: KEO,51 44:11 SNSIZ / KOAe 3; tr 149.6-151.42 C (050; I N NMR (300 MG, SOSIZ)I5 7.88 (4, 2-3.4 Hz, 1NU, 7.47 (8, 3-8.8 Go, 2NU, 7.18 ha, 1-24 Hz, 1H), 6.91-6.86 (t, ЗН), 6.78-6.75 (t, 2H), 6.62 (vv, 1H), 4.26-4.22 (t, 4H)), 3.96 (i, 1-6.5, 2H), 1.82-1.73 (t, 28), 1.56-1.44 (t, 2 NO), 0.98 (i, 31-7.4 Hz, ZN); IS C NMR (75 MHz, SOSIZU6 156.1, 150.8, 143.6, 142.8, 140.2, 139, 9, 139,5,139,2,133,9,130,7,123,1,117,1,115,0, 113,5, 109,4, 68,7, 64,6, 31,6, 19,4, 14,0, IR (NPVV) 3365 st-1; TEZ MS pug 4 | С22НОЗЕМаОЗ NO o

HPLC (Method A) 99095 (ASU -13.2 min. Similarly calculated for C22NOZEM4O3: C, 64.38; H, 5.65; M, 13.65. Found: C, 63.63; H, 5, 60; M, 13.38. 7.3.698 (K929672): Ma-(4-n-hexyloxyphenyl)-M2- | Similar to the preparation of M4-(4-ethyloxyphenyl)-M2-(3,4-ethylenedioxyphenyl)-5- (3,4-ethylenedioxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine, M4-(4-n-hexyloxyphenyl)-M2-(3,4-ethylenedioxyphenyl)-pyridinediamine 5-fluoro-2 ,4-pyridinediamine is restrained as a result of the reaction of 2-chloro-M4-(4-n-hexyloxyphenyl)-5-fluoro-4-pyrimidinamine and 3,4-styrenedioxyaniline. The crude product is purified by chromatography (2: I SNCIZ LETOAc) (0 .22 g, 6995) in the form of a solid phase of a yellowish-red color: KI 0.54 (4: I SNSIZ LEYU As); lir 124.0-125.22 C (05; and H NMR (300 MHz, SOSIZ)5 7.88 (4, 753.2 Hz, 18), 7.47 (4,128.9 Hz, 2H), 7.18 (9, 222.4 Hz, IN), 6.91-6.86 (t, ZNI) , 6.78-6.74 (t, 2NU, 6.62 (4. 1-1.85 by, 1H), 4.26-4.22 (t, 4H), 3.96 (5, 3- 6.5, 2H), 1.83-1.74 (in, 2H), 151-142 (t, 2), 1.36-1.32 (pa, 4H), 0.93-0.89 (1, 3-6,7 Gy, ZNU; 13s NMR (75 MHz, SOSIZ) sem 156.1, 150.5, 143.5, 143.0, 142.8, 150.2, 139.9, 139.5, 139.2, 133.9, 130 ,7. 123.1, 7 o 117, 115.0, 113.5, 109.3, 68.5, 64.7, 64.5, 31.8, 29.5, 29.9, 22.8, 14.25 K (NPVV ) 3378 Article-1; TEZ MS t/» 439 | С2АНОТЕМ4О3 4 I | I; HPLC (Method A) 29995 (AOS) In 214.6 min. Similarly, calculate for С2АНО?ЕМ4О3: С, 65.74; H, 6.21; M, 12.78. They reveal: C, 65.52; H, 6.23; M, 17.66, 7.3.699 (8920818): 5-fluoro-m4-(3-hydroxyphenyl)- / To sumiiz d-amino-((1,2,3,4-tetrazol-5-yl) methyleneoxy | benzene (1.2 g, 6.2 mmol), (Te

M2-144(1,2,3,4-tetrazol-5-yl) I-propanol (40 ml) and trifluoric acid (1 ml) add 2 chloro-5-fluoro-M4-methyleneoxyphenyl-2,4-pyrimidinediamine | (33-Hydroxyphenyl)-4-pyridinamine (1.5 g, 6.2 mmol). The mixture is heated to 110 C for 17 hours, and then cooled to room temperature. The resulting purple solid is filtered off, washed with 1-propanol (30 ml), obtaining 5-fluoro-M4-(3-hydroxyphenyl)-h2-4(4-(1,2,3,4-che letrazol-5 -yl)methyleneoxyphenyl|-2,4-pyrimidinediamine (1.6 g, 6595) in the form of a whitish solid phase: BYA 0.55 (6: 3: I SNSIZ / SNZON / MNYAON); tr (050) Ha 191, 2-193.79 C, 257.2-260.02 C, 344.7-345.22 C; | H NMR (300 MGu, OM5O-a6)5 9.39 (5. EN), 9.21 ( in, 1H), 9.10 (5, IN), 8.04 (8, 1-3.8 Gy, 1), 7.59 (4.459.1 Hz, 2H),

Z5 7.38 (5, 18), 7.23 (71281 Gy, 1H), 7.17 (b, 121.8 Go, 1NU, 7.05 (, 1-8.1 Hz, 15), 6, 93 ge) (y, 1-91 Hz, 2H), 6.50 (ad, 121.8, 8.1 Hz, 18), 5.40 (5, 2H); ISR NMR (75 MGy, pRM5O-4a6)6 157.3, 155.3, 153.5, 151.9, 149.8, 149.7, 141.0 (a, 1C-E-e150.0 Gy), 139 .7, 138.7, 135.0, 128.9, 120.2, 114.8, 110.3, 108.7, 59.6; IC (NPVV) 3338, 2923, 2581, 1724, 1661, 1580, 1557 art-1; TEZ MS put 395 | SIZNIZEM8O2 H 14; TOP. (Method A) 96,595 (AOS), "V. -6.9 min. « 7.3.700 (8920819): M4-(3-hydroxyphenyl)-M2-|4- | To a mixture of 4-amino-HN,1I,2,3,4-tetrazolyl)methyleneoxy|benzene (0.1 g, 0.5 mmol), (IN.I,2,3,4-tetrazole3-1-propanol ( 2 ml) and trifluoric acid (0.2 ml) add 2-chloro-M4-(3- shchyl)methyleneoxyphenyl|-2,4-hydroxyphenyl)-4-pyrimidinamine (0.1 g, 0.5 mmol). The mixture is heated to 1102 s pyrimidineliamine for 17 hours, and then cooled to room temperature. The obtained purple solid substance is filtered, washed with 1- in! with propanol (5 mL) to give M4-4(3-hydroxyphenyl)-M2-144(1H,1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine (59, 4 mg, 3095) in the form of a whitish solid phase: KE 0.51 (6: 3: І SNSIZ / SNZON / MNYAON); tr 292-2957s des;

IN NMR (300 MHz, OM5O-46)5 9.34 (5, 2H), 9.13 (5, IN), 7.95 (4, 125.8 Gy, IN), 7.54 (8. 2-8.9 Hz, 2H), 7.39 (5, 1H), 7.19 0, 328.1 Hz, 19), 7.05 (0, 128.1 Gy, 1H), 6.96 o (db, 3-8.9 Gl, 2), 6.43 (90, 3-14, 8, A So; 18), 6.20 (4, 3-5.8 Sy, 19), 5.40 (5, 2H); 13C NMR (75 MHz, PM50-46)6 160.4, 158.5, 157.5, 154.0, 153.7, 152.2, 140.6, 134.4, 129.1, 120.9, 114 ,7,11,0, 109,5, 107,2, 98,4, 59,6; IC (NPVV) 3321, 2920, ko 758I1, 1649, 1605, 1487 st-!; TEZ MS p/z 377 |(S1YANI6M802 - NO; HPLC (Method

A) 97,696 (АМС), ЕВ. -7.6 min. -y izhnizhanzhchnzhnzhntTtnNzhtzhtzhtchtnTloiltTtTlgyttintnyi (Se) 42) ko 60 b5

7.3.7 (8920820u: M4-(3-hydroxyphenyl)-5- To a mixture of 4-amino-K1H,1,2,3,4-tetrazolyl)methyleneoxybenzene (0.2 g, 0.9 mmol), methyl-M2 -(4-(1H,1,2,3,4-tetrazol-5-I-propanol (4 ml) and trifluoroacetic acid (0.2 ml) add 2-chloro-HM44(3-yl)methyleneoxyphenyl-2.4- hydroxyphenyl)-5-methyl-4-pyrimidinamine (0.2 g, 0.9 mmol).The mixture was heated to pyrimidinediamine at 110 2C for 17 hours and then cooled to room temperature.

The resulting purple solid is filtered, washed with 1-propanol (10 ml), obtaining M4-(3-hydroxyphenia)-5-methyl-M2-I441H,1.2,3,4-tetrazop-5-yl)methyleneoxyphenyl|-2, 4-pyrimidinediamine (0.3 g, 8925) in the form of a whitish solid phase: KU 0.44 (0: 3 1 SNSIZ / SNZON / MNYAO Nu; tr (0503 255.3-262.4 "s; IN NMR ( 300 MHz, UOMI5O-46) 5 10.32 (5, 1H)U, 9.65 (v, 2H), 7.85 (5, 1H), 7.38 (a, 2:10.5 Hz, 2NU , 7.17 (5, IN), 7.12 (6, 27.9, 1), 7.06 (5, 1H)), 6.99 (4, 1-:10.5 Hz, 2H), 6.68 (4.3-7.9 Hz, 1), 5.45 (5, 2H), 2.14 (5, ZN); 13C NMR (75 MGa,

РМ5О0-46)6 161.6, 157.9, 154.5, 153.7, 151.2, 140.4, 138.2, 130.1, 129.4, 123.3, 115.9, 115 ,4,113,5,112,4,107,5, 59,8, 13,7; IC (NPIVV) 3214, 3051, 2157, 1632, 1596, 1547 art-1; TEZ MS t/z 391 (C19NIZM8O2 NO "; HPLC (Method 4) 29995 (AS), "B. -7.9 min. 7.3.7902 Ma4-(3-benzyloxyphenyl)-M2-14-(1-methyl- Mixture M4-(3-benzyloxyphenyl)-2-chloro-4-pyrimidinamine (0.25 g, 0.82 mmol), 4-1,2,3,4-tetrazoa-5-yl)methyleneoxyphenyl |- | amino -(1-methyl-1,72,3,4-tetrazol-5-yl)methyleneoxy|-benzene (0.17 g, 0.82 mmol) and 2,A-pyrimidinamine (necessary K| number of trifluoric acid ( 0.2 ml) in 1-propanol (10 ml) is heated to 1102 for 24 hours. The reaction mixture is evaporated to remove most of the 1-propanol, the crude product is subjected to preliminary adsorption on silica gel using 95: 5 methylene chloride/methanol and purified by flash chromatography (95: 5 methylene chloride/methanol), obtaining M4-(3-benzyloxyphenyl)-M2-(4441-methyl-1,2,3,4-tetrazole-5-1l)methyleneoxyphenyl|-2,4-pyrimidinamine in the form solid phase of whitish color (0.20 g, 5295): IN NMR (300 MHz, ЮМ5О- 946) d 8.00 (Bk 5, 1Н), 7.86 (а, 126.1 Hz, 1), 7.53- 7.20 (iv, 13H), 7.144, 1-9.0 Gv, 2H), 6.93 (a, 7-61 Hz, 1H ), 6.13 (y, 1-61 Сy, 1Н), 5.27 (в, 2Н), 4.04 (5, ЗН); TEZ MS t/x 481 С26Н24М802 и NI 7.3.703 (К920917): MA-(3-hydroxyphenyl)-М2-14- | Sad M4-43-benzyloxyphenyl)-HM2-(4-(1-methyl-1,7,3,4-tetrazol-z-yl) (1-methyl-1,2,3,4-tetrazole-5- methyleneoxyphenyl |-2,4-pyrimidinamine (0.20 g, 0.42 mmol) and 590 Ra/C (0.10 t) in ilumethyleneoxyphenyl|-2,4-pyrimidinamine !a solution of 14:1 ethanol/concentrated hydrochloric acid (40 ml) at room temperature is shaken in a hydrogen atmosphere at a pressure of 3.4 atm. After 3 hours, the absorption of hydrogen stops. The reaction mixture is filtered through an infuser, the solid residues are washed with 95: 5 methylene chloride/methanol, and the filtrate is evaporated, obtaining M4-(3- hydroxyphenyl)-M2-(4-441-methyl-1,2,3,4-c tetrazol-5-yl)methyleneoxyphenyl|-7,4-pyrimidinamine (0.16 g, 9595) in the form of a yellowish-brown solid phase color: KE 0.23 (95: 5 methylene chloride/methanol); tr Ge) (05C) 207.1-212.8, 287.4-295.7 "s; IN NMR (300 MGy, PM5O-d96) d 10.87 (g 5, IN), 10.81 (g 5, IN), 9.62 (be 5, 1H)), 8.08-8.06 (t, 1H), 7.72 (4, 41-90 Hz, 28), 7.24 (Bg z, 1), 7.20-7.00 (t, ZA), 6.61 (t, 2H), 6.45, (y, 3-6 ,0 Go, 1 NU, 5.38 (5 , 2H), 4.40 (5,

ЗН);13С NAM (75 MHz, ОМ5О-46) d 161.3, 160.1, 157.0, 154.3, 151.6, 141.7, 537.6, se 129.1, 128.6, 123 ,4, 114.4, 111.9, 111.5, 108.3, 98.6, 59.6, 38.0; IC (NITVV) 2975, 1639, 1602, 1521st-1; TEZ MS pu 391 | SIZNIYAM8O2 khz NO"; HPLC (Method A) 94995 (AOS, B. -8.19 min. (22 7.3.704 Ma-3-benzyloxyphenyl)-M2-14-(2-methyl- | Mixture M4-4(3-benzyloxyphenyl)-2-chloro -4-pyrimidinamine (0.52 g, 1.69 mmol), 4-"-- 1,2,3,4-tetrazol-5-yl)methyphenoxyphenyl|-|amino-(2-methyl-1,2, 3,4-tetrazol-5-yl)methyleneoxy|benzene (0.34 g, 1.69 mmol) and 72,4-pyrimidinamine (required no. ) is heated to 1102 C for 24 hours. The reaction mixture is evaporated to remove a large amount of I-propanol. The crude product is subjected to preliminary adsorption on silica gel using 95: 5 methylene chloride/methanol and purified by the method of (ee) flash chromatography (95: 5 methylene chloride /methanol), obtaining the target product MA-(3-benzyloxyphenyl)-M2-(4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl)-2,4-pyrimidinamine in the form of a solid yellowish-brown phases (0.41 g, 5195): IN NMR (300 MHz, OM5O-06) d 7.85 (4.5-6.1 g, 1H), 7.49-7.04 (tt , 14H), 6.93 (y, 2-9.0 Gy, 2H), 6.60-6.72 (t, 1H), 6, 11 (8, 156.1 "

Hy, IN), 5.14 (5, 28), 4.34 (in, ZNU; TEZ MS tu/» 481 (С26НО24М802 with NO 7.3.705 (К920910у: M4-(3-hydroxyphenia)-М2-|4 - | A mixture of M4-(3-benzyloxyphenyl)-M2-H4-(2-methyl-1,2,3,4-tetrazole-5- shsh (2-methyl-1,2,3,4-tetrazole-z» yl)methyleneoxyphenyl-2,4-pyrimidinamine (0.40 g, 0.42 mmol) and 595 OC/С 0.10 g) in yl)methyleneoxyphenyl|-2,4-pyrimidinamine | 14:1 ethanol/concentrated saline of acid (40 ml) at room temperature is shaken in a hydrogen atmosphere under a pressure of 3.4 atm. After 3 hours, the absorption of hydrogen stops. The reaction mixture is filtered through filter paper, the solid residues are washed with 95: 5 methylene chloride/methanol, and the filtrate evaporated to give M4-(3-hydroxyphenyl)-M2-(4-(2-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl|-2,4-pyrimidinamine (0.29 mg, 8995 ) in the form of a beige solid phase: КЙ 0.43 (95: 5 methylene chloride/methanol); tr 140-152 20; 1Н o МАМ (300 MHz, РМ5О-46) d 10.24 (g 5, 1Н), 9 .98 (ve 5, 18), 9.52 (og 5, 1), 7.94 (y, 1-6.6 Ha, 2H), 7.54 (4, 18.8 Hz, 2H ), 7.43 (5, 1H), 7.26 (5, IN), 7.18-7.01 (t, ZNU, 6.53, (8, 27.5 Gy, IN, 6.37, (d, 7-56, Hz, 1H), 5.52 (5, 2H), 4.13 (in, ZNU; IZS NMR ko (75 MG, РМ5О-46)d 160.2, 157.2, 154.5, 153.0, 151.2, 146.8, 139.9, 131.8, 128.7, 122.3, 114.7, 111.4, 110.5, 107.5, 99.5, 59.5, 33.3, AK (NIVB) 3042, 1578, 1504, 1459 - art-1; TEZ MS t/h 391 | SIZNIZM8O2 I'm NO; HPLC (Method A) 95.895 (ASU IV. 28.82 min. «se (5920861): 5-fluoro-M4-(3-hydroxyphenyl)- | Mixture of 2-chloro-5-fluoro-M4-(3-thihydroxyphenyl) -4-pyrimidinamiku (0.22 t, 0.93 mmol, 42) ko 60 b5

M2-|441-methyl-1,2,3,4-tetrazole-5-4-amino-C(1-methyl-1,2,3,2-tetrazol-5-yl)methyleneoxy|-benzene (0, 19 g, 0.93 mmol) yl)methyleneoxyphenyl|-2,4-pyrimidinamine | and trifluoroacetic acid (0.2 ml) in 1-propanol (8 ml) is heated to 1102 C for 24 hours. The reaction mixture is evaporated to remove more I-propanol. The crude product is subjected to preliminary adsorption on silica gel using 95: 5 methylene chloride/methanol and purified by Flea chromatography (95: 5 methylene chloride/methanol), obtaining the target product 5-fluoro-M4-(3-hydroxyphenyl)-42-14-( 1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxyphenyl-2,4-pyrimidinamine in the form of a purple solid (0.18 g, 4995): KG 0.47 (95: 5 methylene chloride/ metanoia); tr 219-224 C; 1

NMR (300 MHz, OM5O-46) d 9.36 (z, IN), 9.18 (8, 18), 9.06 (5, 1E0), 8.05 (y, 226.0

Gy, IN), 7.60 (4, 19.0 Hz, 2H), 7.27 (d, 159.0 Gu, 1H), 7.09 (i, 7-8.0 Gy, 2H), 6 .94 (4, 3-90 Hz, 2H), 6.49 (49, 1-80, 2.1 Go, 1E5),, 5.45 (5, 2H), 4.11 (5, ZNU; IZS NMR (75

Mhz, RM5O-y46) d 157.4, 155.5, 151.7, 151.6, 149.6, 149.5, 142.0, 142.0, 139.3 (0, US -E-127 .5 Hz) 135.3, 128.9, 120.1, 114.9, 112.3, 110.3, 198.5, 58.5, 33.95; IC (NPVV) 3278, 1586, 1542, 1508 art-1; TEZ MS ti/z 409 |(С19НИ7ЕМ802 НИ) Kk; SUPER (Method

A) 98.295 (AOS), "A 27.69 min. Similarly calculated for

C19NI7EM8O2-0.5 H2O: C, 54.74; H, 4.23; M. 26,88. They reveal: С, 54,55; H, 4.02;

M, 26.62. 7.3.707 48920860): 5-fluoro-M4-(3-hydroxyphenyl)- | A mixture of 2-chloro-5-fluoro-M443-tihydroxyphenyl)-4-pyrimidinamine (0.31 g, 1.28 mmol), 12-(4-(1-methyl-1,2,3,4-tetrazole-5 - 4-amino-((2-methyl-1,2,3,4-tetrazole-5-zl)methyleneoxy|-benzene (0.26 g, 1.28 mmol) and)methyleneoxyphenyl-2,4-pyrimidinamine | and trifluoric acid (0.2 mL) in 1-propanol (8 mL) was heated to 1102 for 24 hours. The reaction mixture was evaporated to remove most of the 1-propanol. The crude product was preadsorbed on silica gel using 95:5 methylene chloride/methanol and purified by flash chromatography (95:5 methylene chloride/methanol) to give 5-fluoro-M4-(3-hydroxyphenyl)-M2-14-(2-methyl-1,2,3,4-tetrazol-5-yl) )methyleneoxyphenyl|-2,4- pyrimylinamine in the form of a purple solid phase (0.20 g, 3799): VC 0.63 495: 5 methylene chloride/methanol); tr 220-224 C; IN NMR (300 MHz, PM5O- 46) 6 9.36 (5, IN), 9.17 (in, 1), 9.02 (5, IN), 8.05 (4, 722.8 Gy, IN), 7.57 (4, 259.1 Hz, 2H), 7.27 (а, 1-8.0 Hz, INU, 7.10 (ак, 72.8, 5.0 Hz, NI), 6.91 (y, 27-9 ,1 Hz, 2H), 6.49 (yes, 1-8.0,2.8 Hz, IN), 5.29 (5, 2H), 4.39 (5, ЗН); IR C NMR (75 MHz, PM5O-46) d 162.2, 157.4, 155.5, 152.1, 149.6, 149.5, 140.9 (y, IC -E 142.0 Gy), 140.5 , 140.2, 138.7, 134.8, 128.9, 120.2, 114.5, 112.2, 110.2, 108.5, 50.5, 38.5; IC (NIVBV) 3274, 1587, 1507 art-1; TEZ MS t/; 409 IS1I9N17EM802 k NIK; HPLC (Method A) 97.25 (AS), 18. -8.04 min. In a similar way, calculate for SIZN1?EM802,: C, 55.88; MN, Ha 4.20; M, 27.44. Revealed: C, 55,56; H, 4.10; M, 27,17. 7 o 7-3.708 (K920894): Ma-(3-hydroxyphenyl)-5- Mixture of 2-chloro-M4-(3-hydroxyphenyl)-5-methyl-4-pyrimidinamine (0.20 g, 0.85 mmol, methyl-M2-14-(1-methyl-1,2,3,4-tetrazol-4-amino-(1-methyl-1,2,3,4-tetrazol-5-yl)methyleneoxy|-benzene (0 .17 g, 0.85 mmol) and 5-yl)methyleneoxyphenyl|-2,4-trifluoric acid (0.2 ml) in 11-propanol (8 ml) was stirred to 1107C pyrimidine for 24 hours. The reaction mixture was evaporated to remove of most 1-propanol. The crude product is subjected to preliminary adsorption on silica gel using 95:5 methylene chloride/methanol and purified by flash chromatography (95:5 methylene chloride/methanol) to give M4-(3-hydroxyphenyl)-5-methyl -ych2-(4-11-methyl-1,2,3,4-tetrazol-5-yl)umethyleneoxyphenyl|-2,4-pyrimidicamine (e)

In the form of a purple solid phase (0.18 g, 5295): KE0.61 95: 5 methylene chloride/methanol; tr 209-211 C; IN NMR (300 MGy, OM5O-46) 5 9.30 (5, 1H» 8.82 (5, 1H), 8.13 (5, IN), 7.83 (5, 1H), 7.60 (y, 159.0 Gy, NU, 7.18-7.05 (t, ZN), 6.89 (4, 129.0 Hn, 2H), 6.48 (i, 1-7.1 Gu, IN), 5.27 (in, 2H), 4.39 (5, ZNU, 2.08 (5, ZNU; 132 NMR (75 MHz, OMI5O-46) 5 151.7,158.6,157.5,156.7,154.7 , 151.2, 149.2, i. 134.6, 134.6, 128.1, 119.3, 114.0, 112.6, 109.4, 108.9, 104.7, 59.8 .

HPLC (Method A) 96.895 (AOS), (B. 28.23 min. 7.3709 (K920893): M4-(3-hydroxyphenyl)-5- Mixture of 2-chloro-M44(3-hydroxypheni")-5-methyl- 4-pyrimidinamine (0.20 g, 0.85 methyl-M2-(4-(2-methyl-1,2,3,4-tetrazole-mmol), 4-amino-(2-methyl-1,2, 3,4-tetrazo-5-yl)methyleneoxy |-benzene (0.17 g, 0.85 5-1l)methyleneoxyphenyl|-2,4-mmol) and trifluoroacetic acid (0.2 ml) in I-propanol ( 8 ml) is heated to pyrimidineamine P99C for 24 hours. The reaction mixture is evaporated to remove the bitterness of I-propanol. The crude product is subjected to preliminary adsorption on silica gel using 95: 5 methylene chloride/methanol and purified by flash chromatography (95: 5 methylene chloride/ methane), obtaining M4-(3-c hydroxyphenyl)-5-methyl-M2-14-(2-methyl-1,2,3,4-tetrazol-5-yl)methyceneoxyphenyl|- 2,a-pyrimidinamine in the form purple solid phase (0.14 g, 4205): KE 0.44 p z" (95: 5 methylene chloride/methanol); mp 219-221 C; 1H NMR (300 MHz, OM5O-46) 5 ii 9.32 (in, 180), 8.85 (5, 1H), 8.13 (5, 1H), 7.85 (5, 1H), 7.64 (4, 1-9.0 Hz, 2H), 7.20-7.07 (t, ZNU, 6.91 (8, 259.0 Hz, 2H), 6.50 (ad, 7 28.0, 1.2 Hn, 1H), 5.45 (5, 2H), 4.12 (in,

ZN), 2.09 (5, ZN); IZS YAM (75 MGN, M5O-46) 6 158.0, 157.0, 56.I, 154.3, 150.6, 150.0, 39.6, 134.6, 127.5, 118.6, 113 .7, 112.0, 108.8, 108.2, 104.2, 57.4, 32.7, 12.35. IC (NPVV) 3428, 1595, 1567, 1509 st-!; TEZ MS t/h 405 (С20Н2гОМ802 i NIC; HPLC so (Method A) 98.595 (AS), IR 27.89 min. Similarly calculated for

C20nH20Mm802, NO: C, 57.00; H, 5.02; M, 26.59. They reveal: C, 56.86; N, 4.92; M, ko 26.50. 733.710 M2,MA-bis(4- Similar to the method that was used during the experiment, M2,M4- shk ethoxycarbonylmethyleneoxyphenyl)-5- bis(4-ethoxycarbonylmethyleneoxyphenyl)-54(1,2, 3,4-tetrazole-5 -yl)-2,4- (Ce) 42) ko 60 b5

(1,2,3,4-tetrazol-5-yl)-2,4-pyrimidinediamine is restrained as a result of the reaction of M, MA-bis(4-pyrimidinediamine (K925810) ethoxycarbonylmethyleneoxyphenyl)-5-cyano-2,4-pyrimidinediamine and sodium azide.

LC/MS: retention time: 25.8 min; purity: 9570; MS: 535 (МН. 7.3.1 М2-(44(М- Analogously to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-(13-0М» cyclopropylmethylamino)carbonylmethyl | methylamino)carbonylmethyleneoxyphenyl|-2.4- pyrimidinediamine, Me-(4-05-enoxyphenyl)-5-thoxycarbonyl-M4-(3-cyclopropylmethylamino)carbonylmethyleneoxyphenyl|-5-thoxycarbonyl-M44(3-hydroxyphenyl)-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine obtained as a result of the reaction of 5- (8925838) ethoxycarbonyl-M4-(3-hydroxyphenyl)-M2-(methoxycarbonylmethyleneoxyphenyl)-2,4-pyridinediamine with cyclopropylmethylamine. LC/MS: MS (m/z): 478 (MH). 7.3 .712 5-ethoxycarbonyl-M4(3Z-hydroxyphenyl)- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-/3-0M-

M2-44M- methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, 5-ethoxycarbonyl-methylamino)carbonylmethyleneoxyphenyl- | M4-(3-tihydroxyphenyl)-ych2-(4-0M-methylamino)carbonylmethyleneoxyphenyl)-7,4- 70 2,4-pyrimidinediamine (KU25839) pyrimidinediamine is obtained as a result of the reaction of 5-stoxycarbonyl-MA-(3-hydroxyphenyl)- M2-(methoxycarbonylmethyleneoxyphenyl)-2,4-pyridinediamine with methylamine hydrochloride. RH/MS: MS (m/z): 438 (MNK). 7.3.713. . Pyrimidinediamine is obtained as a result of the reaction of 5- (K925840) ethoxy carbonyl-M4-(3-hydroxyphenyl)-M2-(metho oxycarbonylmethyleneoxyphenyl)-2,4-pyridinediamine with 3-amino-1,2-propanediol. RH/MS: MO (m/z): 498 (MN). 7.3.714 im2, Ma-bisTA-1M4(3- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-04- methoxybenzylamino)carbonylmethylene | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, М2,М4-б16/4-ПЧ-(3-siphenyl)|-5-bromo-2,4-pyrimidinediamine | methoxybenzylamino)carbonylmethyleneoxy |phenyl|-5-bromo-2,4-pyrimidinediamine (8925841) is obtained as a result of the reaction of M2,m4-bis|4-ethoxycarbonylmethyleneoxyphenyl)-5-bromo-2,4-pyrimidinediamine with 3-methoxybenzylamine. LC/MS: retention time: 25.94 min; purity: 9595; MS (m/3): 727 (MN). 7.3.715 5-bromo-Ich4-(4-Yi(M- Analogously to the preparation of M4-(3,4 ethylenedioxyphenyl)-5-fluoro-M2-(3-04-cyclopropylmethylamino)carbonylmethyl | methylamino)carbonylmethyleneoxyphenyl|-2,4 -pyrimidinediamine, 5-bromo-Ma-(4-(M- ecoxyphenyl|-M2-(3-hydroxyphentyl)-2,4- pyclopropylmethylamino)carbonylmethyleneoxyphenyl|- M2-(3-hydroxyphenyl)-2,4- pyrimidinediamine (K925842 ) pyrimidinediamine is obtained as a result of the reaction of 5-bromo-M4-(4-ethoxycarbonylmethyleneoxyphenyl)-Ch2-(3-hydroxyphenia)-2,4-pyrimidinediamine and cyclopropylmethydamine. LC/MS: retention time: 20.53 min; purity: 10095; with

MS (m/z): 485 (Mn. at 7.3.716 5-bromo-Ich2-(3-hydroxyphenyl)-M4-(44(M- | Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro -M2-|3-0M- 3- methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimylindiamine, 5-bromo-M24(3- methoxybenzylamino)carbopylmethylenek! hydroxyphenyl)-142-(3-hydroxyphenia)-M4-14-(М -3-siphenyl-2.4-pyrimidinediamine (2925843) | methoxybenzlamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 5-bromo-M4-(4-hthoxycarbonylmethyleneoxyphenyl)-M2-(3-(Te)hydroxyphenyl)-2 . 3-fluoro-M2- | Similar to the preparation of M4-(4-tert-butylphenyl)-5-fluoro-M2-(2,3-dihydro-2-(2-carboxybenzofuran-5-yl)-2,4- carboxybenzofuran- 5-yl)-2,4-pyrimidinediamine, 144 (3,4-etiphenedioxyphenyl)-5-pyrimidinedigamine (KU20698) fluoro-m2-2-carboxybenzofuran-5-yl)-2,4-pyrimidinediamine is obtained as a result of reaction M4 -(3,4-ethylenedi oxyphenyl)-5-fluoro-M2-(2-methoxycarbonylbenzofuran-5-yl2,4-pyrimidinediamine and ION. sem 7.3.718 M2,M4-bis(4-trifluoromethylphenyl)-5- Similar to the preparation of M2-M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (2926016) pyrimidineamine, M2,M4-bis(4-trifluoromethylphenyl)-5-fluoro-2,4-pyrmidineliamine (c c) is obtained as a result of the reaction of 2,4-dichloro-5-fluoro pyrimidine and 4-trifluoromethylaniline. IN NMR (SIZO 8.06 (65, IN), 7.75 a, 2H, 3-9 Hn), 7.67 (4, 2H, 72: 9H2), 7.63 (9, 2H, 12 UNI, 7.54 (a, 2H, 3-9 Gy), 7.19 (05, 1H), 6.96 (5, IN); 19E YAM? (SOSIZ): SI-17598 (5, 35), -17676 (5, 38),-46549 (in, 17U; purity by HPLC: 8595. " 7.3.719 72-(3,4-ethylenedioxyphenyl)-M4-(3,4- Analogously to the preparation of M2-(3-hydroxyphenyl)- M4-(3,4-methylenedioxyphenylhydrazinyl)-5-fluoro-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinamine, M2-(3,4-ethylenedioxyphenyl)-5- 2-pyrimidinamine (5926406) fluoro-m4- (3,4-methylenedioxyphenylhydrazinyl)-2-pyrimidinamine is obtained as a result of the reaction of 2-chloro-5-fluoro M4-(3,4-methylenedioxyphenylhydrazinyl)-4-pyrimidinamine and 3,4-ethylenedioxyaniline. IN NMR (SOZOVKO 7.82 (0 . 14 (a, 1H, 1-24 "g), 6.92 (8, 1H, 2-84 sh), 6.85 (I, 1H, 4-21 and 8.7 1), 6.45 (y , 18, 32: UNI, 6.06 (8, 2Н), 4.10 (5, 4Н); LC/MS: retention time: 12.14 min; purity: 8890; MS (m/z): 426 ( 7.3.720 Ma, ma-bis(4- To solution Diisopropylethylamine (0.200 ml) is added to 2,4-dichloro-5-nitropyrimidine (0.264 g, 1 mmol) in MOAs (19 ml) at a temperature of 0 °C, and then ethyl 4-ethoxycarbonyl-5- nitro-2 4. aminophenoxyacetate (0.585 g, 3 mmol), then shake at room temperature pyrimidinediamine (2926566) for 2 hours. The reaction mixture is cooled by rapid absorption into water and extracted with EI As. The EtOAc extract is washed with 2M HCl. and water The solvent is evaporated, and the residue is purified by crystallization with the use of EIO Ac/hexanes, obtaining M2,M4-bio(4- (Ce) 42) ko 60 b5 ethoxycarbonylmethylenedioxyphenia)-b-stoxycarbonyl-Z-nitro-2,4-pyrimidinediamine (K926566 ). IN NMR (SOSIZ): 10.32 (5, 18), 7.42 (5, TE), 7.40 (40, 2H, 1-8.7 Hz), 7.32 (4.2, 1- 8.7 Hz), 6.93 (0, 2H, 32: 8.7 Hz), 6.82 (0, 2H, 7-8.7 Gy), 4.67 (5, 2H), 4.62 (5, 2H), 4.47 (4. 2H, 3- 7.5 Hz), 4.30 (t, 4H)), 1.42 (I, ЗН, 3- 6.9 Gy), 1, 31 (t, 6H); LC/MS: retention time: 37.10 min; purity: 10095; MS (m/z): 584 (Mn. 7.371721 M2,MA-bis2-(methylthio)-1,3-benzothiaz-6- | Similar to the preparation of M2,144-bis(3-hydroxyphenyl)-5-fluoro-2, 4-yl-5-fluoro-2,4-pyrimidinediamine, IM2,M4-bis|2-(methylthio)-1,3-benzothiaz-o-yl|-5-fluoro-2,4- (85950202) pyrimidinediamine obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrcmidine and 2-(methyliso)-1,3-benzothiazole-b-amine, LC/MS: retention time: 24.98 min, purity: 84.65; MS (m/z): 486.80 (M). 7.3.722 Ma-134(2-hydroxyethylamino)phenyl|-M2- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-Mm2-( 13-(M-

H3-(M-(M-methyl)» methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine, M4-I|3-4(2- piperazino)carbonylmethyleneaminophenyl | hydroxyethyleneoxy)phenyl|-M2-|340M-(M-methyl)-1-5-fluoro-2,4-pyrimidinediamine (K950240) | piperazino)carbonylmethypenaminophenyl-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M2-(carboxymethyleneaminophenyl)-5-fluoro-M4-Y3-2-hydroxyethylamino)phenyl|-2,4-pyrimidinediamine and M-methylpiperazine. LC/MS: retention time: 13.36 min; purity: 97.65; MS (m/z): 495.42 (MN). 7.3,723 Mma-13-(2-hydroxystiledamino)phenia|-M2- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-II34(M-

I3-(M-piperazino)-methylamino)carbonylethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3-(2-carbonylmethyleneaminophenyl|-5-fluoro-hydroxyethyleneamino)phenyl|-M2-13-(M-piperazino)-carbonylmethyleneaminophenyl |- 2.4-pyrimidinediamine (KU50241) 5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M2-(carboxymethyleneaminophenyl)-5-fluoro-M4-(3-(2-hydroxyethyleneamino)phenyl|-2,4-pyrimidinediamine and piperazine. LC/MS: retention time: 13.21 min; purity: 100; MS (m/z): 481.40 (MH). 7.3.2A (Syn ma-(3-aminophenyl)-5-fluoro-m243 -43- | Ma43-aminophenyl)-5-fluoro-142-(3-(3-carboxy-3-0.1Am.carboxy-3-YUM-M-phtapoylamino)propylenecarbonylaminophenia)-2 4-pyrimidinediamine is obtained in phthaloylamino )propylenecarbonylaminophe | as a result of the reaction of M2,M4-bis(4-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and M-nyl)-2,4-pyrimidinediamine (K950251) with phthaloyl)I-anhydride of glutamic acid in DMF . PH/MS: retention time: 19.41 min; purity; 95.75, MO (m/zu; 569.98 (MH U). 7.3.725 (-m4-(3-aminophenyl)-5-fluoro-14Ch2-(3-(3- | M4-(3-aminophenyl) )-5-fluoro-M2-(3-(3-carboxy-3-carboxy-3-amino)propylenecarbonylaminophenyl|-2,4-pyrimidineliamine is obtained as a result of amino)propylenecarbonylaminophenyl|-2,4- | reaction ()- M4-(3-aminophenyl)-5-fluoro-M2-13-(3-carboxy-3-0,1-h-pyrimidinediamine (5950255) phthaloylamino)propylenecarbonylaminophenyl|-2,4-pyrimidinediamine and hydrazine. Ge)

VA/MS: retention time: 11.98 min; purity: 90.195; MC (m/z): 440.3 (MN.E). 7.3,726 5-methoxycarbonia-M2,IM4-bist(M. Analogous to the preparation of IM4-(3,4-ethylenedioxyphenyl)-5-fluoro-2-|3-(M- pyrrolidino)carbonylmethyleneoxyphenyl)- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 5-methoxycarbonyl-2,4-pyrimidinediamine (KU26559) M2,ma-bio(4-(M-pyrrolidino)methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction 5-stoxycarbonyl-2х4-bi((4-methoxycarbonylmethyloxyphenyl)-2,4-pyrimidinediamive and pyrrolidine.

The ethyl ether in the 5-position is replaced by the methyl ether in (e") methanol as a solvent. MS (m/z)y: 575 (MN). 7.3.727 M2,M4-bis(4- Analogous to the preparation of M2.1х4-bis(3-hydroxyphenyl)-5-fluoro-2,4- or ethoxycarbonylmethyleneoxyphenyl)-5-pyrimidinediamine, M2,M4-bis(4-ethoxycarbonylmethyleneoxyphenyl) - 5-fluoro-2,4-fluoro-2,4-pyridinediamine (K925565) pyridinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine with Ha! ethanol with 4-aminophenoxyacetate.. MS (m/z): 485 (MH). 7.3,728 M2-(3-ethoxycarbonylmethyleneoxyphenyl)- | Similar to the preparation of M2-(3-hydroxyphenyl)-M4-(3,4-ethylenedioxyphenyl)-5-(ee) 5-ethoxycarbonyl-M4-(3,4-fluoro-2,4-pyrimidinamine, M2-(3-ethoxycarbonylmethyleneoxyphenyl) )-5-tetrafluoroethylenedioxyphenyl)-2,4-ethoxycarbonyl-M4-(3,4-tetrafluoroethylenedioxyphenyl)-2,4-pyrimidinediamine pyrimidinediamine (K926799) is obtained as a result of resection of stil 3-aminophenoxyacetate and 2-chloro-5-ethoxycarbonyl-4 -(3,4-tetrafluoroethylenedioxyphenyl)-4-pyrimidinamine. MS (m/z): 567 (MH). " 7.3.729 M4-3,4-ethylenedioxyphenyl)-5-fluoro-M2- To a solution of 3-0)-biotin and M4-3,4-styrenedioxyphenyl)-5-fluoro-m2-13-7M-2- ( of hydroxyethylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in DMF with 2 biotinylethylaminocarbonylmethyleneoxy | lyisopropylethylamine is added at a temperature of -20 oC, and the mixture is shaken for phenyl|-2,4-pyrimidinediamine (KU26811) for 19 minutes. Benzotriazol-1-yl-oxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOR) is added to this mixture, after which the mixture is shaken at room temperature for 24 hours. The reaction is quenched with water and extracted with ethyl acetate. The ethyl acetate extract is washed with an aqueous solution of Manso)Z, and then with water. The precipitate obtained after removing the solvent is purified by preparative TLC, obtaining M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-|3-(M-2-(B)-C)-biotinylethylamino|carbonylmethyleneoxyphenyl)-2, 4-pyrimidinediamine. with RH/MS: retention time: 19.29 min; purity: 9995; MS (m/z): 682 (M). 7.3.130 5-fluoro-M4-(3-hydroxyphenyl)- M212-(M- Analogous to the preparation of M4-(3,4-ethylenedioxypheny)-5-fluoro-YM2-|3-(M- methyl-M-2- methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-M4-(3- co hydroxyethyl)carbonylbenzofuran-o-yl)- | hydroxyphenyl)-M2|2-(M-methyl-M-2-hydroxyethyl)carbonylbenzofuran-5-yl)-2,4- 2,A-pyrimidinediamine (KU26725) pyrimidinediamine is obtained as a result of the reaction of 5-fluoro-M4-(3 -hydroxyphenyl)- and M2|2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinedimine and 2-0M-methyl)ethanolamine. LC/MS: retention time: 14.87 min; purity: 9895; MS: 20 438 (MN). (Se) 42) ko 60 b5

7.3.731 2,m4-bis(3-ethoxycarbonylphenyl)-5- Analogous to the preparation of М7,М4-bis(3-thyloxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (1926228) pyrimidinediamine, ІМ2 ,M4-bis(3-ethoxycarbonylpheny)-5-fluoro-2,4-pyrimidinedimine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-ethoxycarbonylaniline. LC/MS: retention time: 26.55 min; purity: 10095;

ME (m/z): 425 (MN). 7.311732 M2-(Z-chloro-d-methylbenzyl)-M4-(3,4- Similar to the preparation of M2-(3-tihydroxyphenyl)-M4-(3,4-ethylenedioxyphenyl)-5-ethylenedioxyphenyl)-5-fluoro-2 ,4-fluoro-2,4-pyrimidinamine, M2-(3-chloro-4-methylbenzyl)-m4-(3,4-ethylenelioxyphenia)-pyrimidinediamine (2908696) 5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction 2-chloro-M4-cetylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3-chloro-4-methylbenzylamine.

LC/MS: retention time: 25.38 min; purity: 9990; MS (m/1): 401 (MN. 7.3.733 (kuma-(3,4-ethylenedioxyphenyl)-5-fluoro- | Analogous to the preparation of M2-(3-hydroxyphenyl)-M4-(3,4-ethylenedioxyphenyl)- 5-142-(2-phenylethyl)-2,4-pyrimidinediamine fluoro-2,4-pyrimidinamine, (7)-M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(2- (K9086973 phenylethyl) -2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and (5)-2-aminoethylbenzene.

PH/MS: retention time: 23.48 min; purity: 9995, MS (m/z): 367 (MN). 7.3.134 M2-(3-ethoxycarboniaphenyl)-M44(1,4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-ethylenedioxyphenyl)-5-fluoro-2,4-hydroxyphenyl )-2,4-pyrimidinediamine, M2-(3-ethoxycarbonylphenyl)-4-(3,4-pyrimidinediamine (2925745) ethylenedioxyphenyl)-5-fluoro-?,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M443,4 -ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3-stoxycarbonylaniline. IN NMR (SOSIZUO 8.04 (Be, 18), 7.94 (e, 1H), 7.90 (Bi, 1H), 7.68 (Ba, 1H, 2-:7.5 Hz), 7, 35(6 1H, 428.1 Gy), 7.28 (a, 1, P- 4 Hz), 7.07 (5, 1), 6.93 (44, 1H, З and 8.7 Hz), 6, 83 (4, 1H, U: 9 Go), 6.64 (v, 1H), 4.36 (a, 2H, 12 7.2 Hz), 4.26 9s, 4H), 1.35 (i, ЗН, 7»: 7.5 Hz); 19E NMR (SOSIZ):-47247; LC/MS: retention time: 15.88 min; purity: 10095; MS (m/z): 41 (MN). 7.3.735 m4-(3,4-difluorophenip)-5-fluoro-M2-13-0M- | A solution of M-methyl 3-aminophenoxyacetamide (1 equivalent) and 2-chloro-M4-(3,4-methylamino)carbonylmethyleneoxyphenyl|- | difluorophenyl)-5-fluoro-4-pyrimidinamine (1.2 equivalents) in MEOH is shaken in 2,4-pyrimidinediamine (K920394) in a hermetically sealed flask at a temperature of 100 o C for 24 hours. After cooling to room temperature, the mixture is dissolved in ethyl acetate.

The obtained solid is filtered and washed with a mixture of ethyl acetate:n-hexanes (1:1; by volume), obtaining M4-(3,4-difluorophenyl)-5-fluoro-ych2-|3-(H-methylamino)carbonylmethyleneoxyphenyl| -2,4-pyrimidinediamine. 1

NMR (0M50-46u:0 10.05 (8, 1), 9.83 (05, 1NU, 8.23 (4, 1Н, 2- 2.7 Gy), 7.98 (t, 2NU 7.52 (t, IN), 7.39 Ohm, IN), 7.20 (t, ZN), 6.60 (tp, 1H), 4.37 (v, 2HO, 2.63 (d, ZN, sem 1 -33 Hu; LC/MS: purity: 9495; MS (m/z): 404 (MEN). 7 o 7.3.736 ma-(4-chlorophenyl)-5-fluoro-M2-13-(1M-) Similar to preparation M4-(3,4-difluorophenyl)-5-fluoro-m2-13-(m-methylamino)carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenia)-2,4-pyrimidinediamine, M4A-(4-xorphenia)-2,4- pyrimidinediamine (K920396) 5-fluoro-M2-13-0M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide with 2-chloro-Ma-(4-chlorophenyl)-5-fluoro -4-pyrimidinamine. IN NMR (OM 5O-Y62 10.21 (B5, 1, "se 10.00 (Be, 1), 8.26 (0, 1H, 1-48 Hz), 8004, 1, 7 - 4.2 Hz), 7.77 (44, 2H, 1-21 and 7.6 Hz), 7.37 (ab, 2H, U 2.1 and 7.6 Hz), 7.17 Um, ЗН ), 8.63 "44, 1H, 2: 1.8 and 8.1 Gy), 4.37 (8, 2H), 2.64 (y, ZN, 4.5 Go); LC/MS: purity : 9295; MS (m/z): 402 (MH). (o) 7.3.736.1 Mmach3,4-dichlorophenyl)-5-fluoro-IM2-(3 404-| similar to the preparation of М4-(3 4-difluorophenyl)-5-fluoro-М2-13-(М-methylamino)carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3,4-h-2,4-pyrimidinediamine (K920397) dichlorophenyl)-5-fluoro-M2-|3-(M-methylamino)carbonylmethyleneoxyphenia|-2, 4-pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-sem aminophenoxycetamide with 2-chloro-M4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidinamine. 1 NMR (OM 5O-46) 7 10.02 (B5, 1H1), 9.76 (B5, 18), 8.24 (9, 1H, 1-4.2 Hz), 8.08 s ( t. ZN), 6.58 (t, 1H), 4.36 (5, TA), 2.63 (4, IN, 1: 2.7 Hm); LC/MS: purity: 9195; MS: 434 (MN. 73737 5-fluoro-M4-(5-methyliridan-2-11)-I42-Y3-. | Similar to the preparation of M4-(3,4-difluorophenia)-5-fluoro-M2-(3- (M- (M methylamino)carbovylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-M4-(5- « methylamino)carbonylmethyleneoxyphenyl-|methiapyridmn-2-1l)-M2-13-(M-methylamino)carbonylmethyleneoxyphenyl-2 ,4-2,4-pyrimylindismine (920398) pyrimidinediamine is obtained as a result of the reaction of M-methnyl 3-aminophenoxyacetamide with 2-chloro-3-fluoro-M4-(5-methylptyridin-2-yl)-4- with pyrimidineamine. NMR (OM5O0-Y6KO 11.35 (B, IN), 10.70 (B5, 1H), 8.58 (5, 1H), 8.42 (4.1H, 72 3.0 Hz), 8.12 (B, IN, 1- 9.3 Hz), 8.03 (ra, 1Н, 7 4.2 Hz), 7.82 (d, n IN, 8.7 Gy), 7.56 (8, 1Н ), 7.30 (vad, IN, 2 8.1 Hz, 7.19 ( IN, /- 8.1 Gy), 6.55 and » (84, 1H, I 1.8 and 8.1 Hz) . (Mk). 7.3.738 5-fluoro-M4-(6-methylythyridin-2-yl)-M2-Y3- | Similar to the preparation of M4-(3,4-difluorophenyl)-5-fluoro-M2-(34(M - (M-methylamino)carbonylmethyleneoxyphenyl)-2,4- pyrimidinediamine, 5-fluoro-144-(6-methylamino)carbonylmethyleneoxyphenyl|- | methylpyridin-2-yl)-M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4- o 2,4-pyrimidinediamine (929399) pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide with 2-chloro-5-fluoro- M4-(6-methylpyridin-2-yl)-4-ko pyrimidineamine. TYA NMR (0M5O-46kO 19.00 (b5, 18), 9.60 (b5, 18, 8.25 (8, 1H), 7.95 (t, ZNO), 7.30 (5, IN), 7.10 (it, ZNO, 6.55 (94, 1H, /- 7.2 Ha), 4.40 (5. 2), 2.62.(8, -' ZH, I1- 3.6 Gy ), 2.45 (5, ZNU; RH/MS: purity: 925; MS (m/z); 383 (MN). (Se) (42) ko 60 b5

7.3.739 M4-(5-chloropyrylin-2-1l)-5-fluoro-M2-(3- | Similar to the preparation of M4-(3,4 difluorophenyl)-5-fluoro-yM2-(3-(M. (M - methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4-(5- methylamino)carbonylmethyloxyphenyl)- | chloropyridin-2-yl)-5-fluoro-142-Y3-(M-methylamino)carbovylmethyleneoxyphenyl|-2,4- 2 ,4-pyrimidinediamipe (8920405) pyrimidineliamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide and 2-chloro-M4-(5-chloropyridin-2-yl)-5-fluoro-4-pyrimidinamine. 1H NMR (0M50-46) y:7 10.04 (65, IN), 9.53 (B5, 1), 8.40 (4, 1H, 1-2A g), 8.22 (t, 2H), 7.88 (Ba, 1H, 7: 4.5 Gy), 7.86 (84, 1H, 7- 2.4 and 8.7 Gy), 7.40 (d, 1H, 151.8 Gy), 7.19 (t, 2H), 6.51 (Bad, IN, 7- 1.2 and 9 Hz), 4.38 (5, 2H), 2.64 (d,

ZN, 12 3.3 Gy); LC/MS: purity: 955; MS (m/z): 403 (Mk). 7.3.740 M4-(6-chloropyridin-3-yl)-5-fluoro-M2-13- | Analogous to the preparation of M4-4(3,4-difluorofeyl)-5fluoro-M2-(3-(M- (M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(6-methylamino)carbonylmethyleneoxyphenyl)- | chloropyridine- 3-yl)-5-fluoro-M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl l|-2,4-2,4-pyrimidinediamine (K920406) pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide and 2-chloro- M4-(b-chloropyridin-3-yl)-5-fluoro-4-pyrimidinamine. NN NMR (0М50-46Х 1 9.72 (5, 1Н), 9.38 (8, 1Н), 8.93 (1, 12 3.0

Hz), 8.28 (pi, 1H), 8.18 (4, IN, 7" 3.6 Hz), 7.95 (t, 1H), 7.45 (4, IN, 7- 8.7 Go), 7.39 (t, IN), 7.21 (t, 1H), 7.14 0, IN, 7- 4.8 Hyd), 6.50 (Bai, 1H, 2: 7.8 Gy ). 4.4 (5, 2H, 2.83 (d, ZNU; LC/MS: purity: NOI; MS (m/z): 403 (MN x). 7.3.741 5-fluoro-M2-I34(M- Similarly to the preparation of 144-(3,4-difluorophenyl)-5-fluoro-M2-13-(M-methylamino)carbonylmethyleneoxyphenyl- | methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, 5-fluoro-M2-I3-(M-

Ma-(4-methylpyridin-2-1l)-2,4-methylamino)carbonylmethyleneoxyphenyl)-M4-(4-methylpyridin-2-yl)-2,4- pyrimidinediamine (8927016) pyrimidinediamine is obtained as a result of the reaction of M-methyl 3 - aminophenoxyacetamide from 2-chloro-5-fluoro-M4-(4-methylpyridine-2-1l)-4-pyrimidinamine. LC/MS: purity: 9595; MS (m/z): 383 (MN). 7.3.742 5-fluoro-M2-I34(M- Analogously to the preparation of M4-(3,4-difluorophenyl)-5-fluoro-M2-13-(M- methylaminocarbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine . 3-aminophenoxyacetamide with 2-chloro-5-fluoro-M4-(3-trifluoromethylphenyl)-4-pyrimidinamine. IN NMR (0M50-46):01 9.835 (Bv, I NU, 9.54 (Bv, 1H), 8.204 , 1H,

Be 3.6 Hz), 7.94 (t, 2H), 7.78 (65, 12), 7.53 0. 1, 3- 8.4 u), 7.25 (t 28), 7.15 (,

IN, 7.5 Go), 7.03 (va, IN, 7-9.3 Hz), 6.55 (Ba, IN, 2-7.5 Hn), 4.36 (z, 2H), 2 .63 (4,

ZN, re 4.5 Hz); LC/MS: purity: 9195; ME (m/zu: 452 (MN). 7.3.743 Ma-(3,4-difluoromethylenedioxyphenyl)-5- | Similar to the preparation of M4-(3,4-difluorophenyl)-5-fluoro-M2-I|340Mch- s fluoro-M2-(3-(M- methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3,4- methylamino)carbonylmethyleneoxyphenyl|- | liftormethylenedioxyphenyl)-5-fluoro-M2-|3-0M- about 2.4 -pyrimidinediamine (KU20408) methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide with 2-chloro-M-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine. IN NMR (OM 50-46): 9.91 (65, IN), 9.64 (v5, 1H), 8.19 (4, 1H, 7- 3.9 Gy), 8.03 (5, 1H ), 7.96 (Va, IN, 1-48

Gi), 7.46 (t, 18), 7.36 (y, 1H, 1-5 8.7 Hz), 7.27 (5, 1NU, 7.17 (t, 2, 6.57 (wai , TA, (Ce) 1-7.2 Gm), 4.36 (5, 111), 2.62 (y, ZN, 7- 4.5 Hu); LC/MS: purity: 9699; MS (m /z); 448 (МН). : Ф 7.3.7144 Ma-(3-chloro-4-trifluoromethoxyphenyl)-5- Similar to the preparation of M4-4(3,4-difluorophenyl)-5-fluoro-M2-13-( M- fluoro-M2-I3-40M-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine, 44-(3-chloro-4-che methylamino)carbonylmethyleneoxyphenyl|- | trifluoromethoxyphenyl)-5-fluoro-M2-I3-(M -methylamino)carbonylmethyleneoxyphenyl|- 2.4-pyrimidineliamine (K920410) 2.A4-pyrimidonediamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide and 2-chloro-MA-(3-chloro-4-trifluoromethoxyphenia)-5-fluoro-4- se lyrimidineamine. IN NMR (СО3ОО 8.084, 1.3-5.4 Gy), 7.994, 1Н, 3-36

Gy, 7.67 (09, IN, - 2.4 and 950 Gy), 7.40 (t, ZN), 7.06 (t, 2), 6.92 (84, 1H, 155 2.4 and (ee) 8.4 Hyd), 4.44 (5, 2H), 2.80 (5, ZNU; I9E NMR (SPZOYU): -16973 and -45983; LC/MS: purity: 9655; MS (m/ z): 486 (МН ю). 7.3.745 M4-(4-ethoxyphenyl)-5-fluoro-Ich2-Y3-(M- Analogous to the preparation of IM4-(3,4-difluorophenyl)-5-fluoro-M2-13 -(M- mechylamino)carbokylmethyleneoxyphenia|- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(4-ethoxyphenyl)» 2,4-pyrimidinediamine (KU26827) 5-fluoro-M2-I3-(M-methylamino) carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine " is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide and 2-chloro-M4-(4-ethoxyphenyl)-5-fluoro-4-pyrimidinamine. LC/MS: purity: 9635; MS: 412 (MNYAYU). shsh c 7.3.746 74-(3,4-ethylenedioxyphenyl)-5-fluoro-YSHM2- | Similar to the preparation of M4-(3,4-difluorophenyl)-5-fluoro-M2-13-(4- (4-methoxy-3-4(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4-(3,4-p methylamino)carbonylmethyleneoxyphenyl- | stylenedioxyphenyl)-5-fluoro-IM2-(4-methoxy-3- 04- and t 2,4-pyr imidinediamine (К926828) methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-amino-6-methoxyphenoxyacetamide with 2-chloro-M4-43,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine. TN NMR (SOZO12): P 7.83 (5, 1), 7.80 (4.1H, 2124.2 g), 7.30sa, IN, 2.4 Gy), 7.23 (9, 1H, A 2 ,4 Gy), 7.06 (t, 2H), 6.90 (41, g 5.7 Hz), 6.734, 1H,1- 5.2 Gy), 4.32 (5, 2H), 4, 22 (5, 4NI), 3.86 (5, ZN), 2.83 (ee) (5, ZNU VH/MS: purity: 9795; MS (m/zu: 455 (MN.Y). 7.3.7А7 5-fluoro-M4-(3-hydroxyphenyl)-I2-(4- Analogous to the preparation of M4-(3,4-difluorophenyl)-5-fluoro-M2-Y34(M-kz methoxy-3-(M-methylamino)carbonylmethyleneoxyphenyl -2,4-pyrimidinediamine, 5-fluoro-M4-(3-methylamino)carbonylmethyleneoxyphenia|- | hydroxyphenyl)-M2-H4-methoxy-3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4- shk 2.4-pyrimidinediamine ( KU26829) pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-amino-4-(Ce) (42) co 60 b5 of methoxyphenoxyacetamide with 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine. IN NMR ( SOZOBH: GI 7.86 (6, 18, 1 4.2 Hn), 7.35 (4, 1H, 7- 2.4

Hz), 7.19 (t, 1H), 7.12 (t, ZA), 6.93 (0, IN, 3-8.7 Hz), 6.52 (t, 1), 4.37 ( 5, 28), 3.85 (5, ZN), 2.82 (5, ZN); 191 NMR (SUOZOG):-47650; LC/MS: purity: 10090; MC: 414(MNU. 2 7.3.748 Ma-(3-chlorophenyl)-5-fluoro-M2-13-0Ch- Similar to the preparation of 144-(3,4-difluorophenyl)-5-fluoro-M2-13-(h - methylamino)carbonylmethyleneoxyphenyl- | methylamino)carbonylmethyleneoxyphenyl 1)-2,4-pyrimylyvdiamine, M4-(3-chlorophenyl)- 2,4-pyrimidinediamine (926832) 5-fluoro-M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl)- 2,4-pyrimidinediamine is obtained as a result of the reaction of 3M-methyl 3-aminophenoxyacetamide and 2-chloro-M4-(3-chlorophenyl)-5-fluoro-4-pyrimidineamine. /H NMR (OM 50-46): 0 10.12 (z, 1H)), 9.93 (8.18), 8.27 (4, 1H, 34.2 Ga), 7.98 (9, IN, 1- 4.9 Hz), 7.85 (5, 1H), 7.73 (dO, 1H, 1 8.1 Gy), 7.35 (0 EN, 1- 8.4 Gy), 7.19 (t, Z), 6.62 (ip, 1H), 4.36 (5, 28), 2.63 (4, ZN, 70 1-42 Hn); LC/MS: purity: 9595; MS: 402 (MINYU). 7.3.749 5-fluoro-M4-(3-methoxy-5- Analogous to the preparation of IM4-(3,4-difluorophenyl)-5-fluoro-M2-13-(0M- trifluoromethylphenyl)-M2-13-(0M4- methylamino )carbonylmethyleneoxyphenyl)-2,4-pyrimylindiamine, 5-fluoro-M4-(3-methylamino)carbonylmethyleneoxyphenyl|- | methoxy-5-trifluoromethylphenyl)-M2-|3-(M-methylamino)carbonylethyleneoxyphenyl|- 2,4-pyrimidinediamine (5926833) 2,4-pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide and 2-chloro-5- fluoro-IM4-(3-methoxy-5-trifluoromethylphenyl)-4-pyrimidinamine. LC/MS: purity: 9595; MS (m/z): 466 (MN). 7.3.750 5-fluoro-Ма-(3-hydroxy-4-methoxyphenyl)- Analogous to preparation M4-(3,4-difluorophenyl)-5-fluoro-М2-І34(М-

M2-134(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidivdiamine, 5-fluoro-ma4-(3-methylamino)carbonylmethyleneoxyphenyl|- | hydroxy-4-methoxyphenyl)-m2-(340M-methylamico)carbonylmethylhexoxyphenyl|-2,4- 2,4-pyrimidinediamine (KU258384) pyrimidinediamine, obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide and 2-chloro-5-fluoro- M4-(3-hydroxy-4-methoxyphenyl)-4-pyrimidinamine. "H NMR (OM5O0-4y6u: 6 9.70 (bv, 2NU, 8.12 (4, 1Н, 1- 4.8 Hz), 7.96 (t, 1NU, 7.12 (t, 5Н), 6.85 (a, IN, /-: 8.7 Hz), 6.57 (Ba, 1H, 1- 8.1 Hz), 4.35 (c, 2), 3.74 (5, ЗН) . - Similarly to the preparation of M4-(3,4-difluorophenyl)-5-fluoro-M2-(3-(M-trifluoromethylphenyl)M2.134(M-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine, 5"fluoro-M4- (4-methylamino)carbonylmethyleneoxyphenyl|-|methoxy-3-trifluoromethylphenyl)-M2-|3-(M-methylamino)carboniamethyleneoxyphenyl-2,A-pyrimidinediamine (K926835) 2,4-pyrimidinediamine is obtained as a result of the reaction of M-methyl 3- aminophenoxyacetamide and 2-chloro-5-fluoro-M4-(4-methoxy-3-trifluoromethylphenyl)-4" pyrimidineamine. "NAM (pM50-46): 5 9.9 B5, IN), 9.62 (B5. 18 ), 8.17 (4, 1H, I-sem 4.2 Hn), 8.04 (Bad, IN, 12 7.2 Hz), 7.82, 1H, 2.7 Gy), 7.18 (t, ЗН), 7.11 (0 16, 1-81 g), 6.55 (64, IN, 1- 6.9 Hz); 4.33 (5, 2Н), 3.86 (in, ЗН), 2561 ( 4, ЗН, 154.0 ГИ); at 20201000 2 1 R mozyyutouk to my . methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, 5-fluoro-M4-(4-fluoromethylamino)carbonylmethyleneoxyphenia|- | 3-trifluoromethylphenyl)-M2-13-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4- (Che) 2,A-pyrimidinediamine (K926838) pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamyl and 2-chloro-5- fluoro-Ma4-(4-fluoro-3-trifluoromethylphenyl)-4-b pyrimylicamine. "YAN NMR POM50-i6): 5 9.80 (5, 1H), 9.44 (z, 1H), 8.25 (t, IN), 8.18 (4, 1H, 7-39 Hz), 8.00 (t, 18), 7.97 (t, IN), 7.47 (i, IN, 1: 9.6 Gy), 7.26 (5, 18), 7.21 (t, NU , 7.11 0, 1H, 2- 8.4 Hn), 6.51 (4, IN, 1: 9.9 Hz), 4.34 (5, 2H), 2.62 (4, or

ZN, I 4.8 Gu); LC/MS: purity: 8895; MS: 454 (MN). 7.3.753 Ma-4(3-chloro-4-methylphenia)-3-fluoro-M2- Analogous to the preparation of M4-(3,4-difluorophenyl)-5-fluoro-1m2-13-04- and.

I3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3-chloro-4-methylamino)carbonylmethyleneoxyphenyl- | methyphenia)-5-fluoro-m2-Y3-(M-methylamino)carbonylmethyleneoxyphenyl)-2,4-(ee) 2,4-pyrimidineliamine (К926839) pyrimididiamium is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide and 2-chloro-M4- (3-chloro-4-methylphenyl)-4-pyrimidinamine. /N

NMR (0M50-46): 6 9.69 (5.1), 9.52 (5, IN), 8.16 (d, IN, 1-4.2 Hz), 7.96 (5, 18), 7 ... 54 (L4, IN, 127.2 Hz), 4.34 (5, 2H), 2.63 (0, ЗН, 15 4.2 Gy), 2.27 (5, ЗН); LC/MS: " purity: 8095; MS (m/z): 415 (M. 7.3.154 1Ма-(2-chloro-5-methylphenyl)-5-fluoro-M2- Analogous to М4-(3,4-lifluoropheny)-5- ftov-m2-13-(M- shshch

I3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(2-chloro-5-methylamino)carbonylmethyleneoxyphenyl)- | methylphenyl)-5-fluoro-M2-(3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4- 2,4-pyrimidinediamine (K925840) pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-h with aminophenoxyacetamide and 2-chloro- MA-(2-chloro-5-methylphenyl)-4-pyrimidinamine. "NN" NMR (0M50-46): 5 9.80 (Be, NU, 8.21 (4, IN, 2-48 Hz), 7 .92 (4, 1H, 1- 4.8 Hu, 7.46 (t, 1H), 7.31 (t, 2H), 7.04 (t, 2H), 6.53 (y, 1H, 7 8.1 Gy), 4.30 (5, IN), 2.18 (5, ZN); LC/MS: purity: 9395; MS (m/z): 416 (MN. 35 7.3.155 MA-( 3,4-ethylenedioxyphenyl)-5-fluoro-M2- As a result of the reaction of M4A-(3,4-ethylenedioxyphenyl-5-fluoro-M2" (ee) IZ-(- (ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine with isopropylamine ( 5 isopropylamino)carbonylmethyleneoxyphene | equivalents) in the presence of diisopropylethylamine (5 equivalents) in MEOH in

KkZz ily-2,4-pyrimidinediamine (5926830) in a thermally closed flask at a temperature of 802C for 24 hours is obtained

M443,4-ethylenedioxyphentyl)-5-fluoro-Mm2-I13-4(M--k isopropylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidindiamine. "NN NMR (РМ5О0-46): 5 9.15 (5, IN), 8.04 (4, 1Н, Re 4.2 Ga), 7.77 (8, 1Н, 12 7.5 Hu), 7.28 (t , 48), 7.08 (B1H. 27: 8.1 Gm), 6.78 (y, 18, 72 8.7 Go), 6.45 (04, IN, 7- 1.8 and 7.8 Hz) , 4.30 (5, 28), (Se) 42) (F, ko 60 b5

4.205, 4H), 3.92 (t, 1H), 1.05 (a, OH, 1-6.6 Gy); LC/MS: purity: 9595; MC (m/z): 454 (MN. 7.3.156 M2-134(M- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-4(M-cyclopropylamino)carbonylmethyleneoxy | isopropylamino )carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-M4-(3,4-phenyl|-M4-(3,4-ethylenedioxyphenyl)-5-ethylenedioxyphenyl)-M2-I3-(M-cyclopropenpilamino)carbonylmethyleneoxyphenyl| -2,4-fluoro-2,4-pyrimidinediamine (KO26848) pyrimidinediamine is obtained as a result of the reaction of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine with cyclopropylamine. "H NMR ( RIM8O-66): 6 9.17 (bv, 2H), 8.05 (t, 2), 7.27 (t, 4NU ovi, 3-81 Gy), 76741, 1- 8.7 Hz), 6 .42 (ab, 18, 3-24 and V.I Sn), 4.3 (5, 2NI), 4.2 (б5, 1Н), 2.65 (t, IN), 0.6 (t, 2H), 0.45 (t, 2H); LC/MS: purity: 9195;

Me (mu; 452 (МН. 70 73.757 М44(4-cyano-3-methylphenyl)-5-fluoro-М2- | Analogously to the formula M4-(3,4-difluorophenyl)-5-fluoro-М2-ІІ340М-

I3-(- methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(4-cyano-3-methylamino)carbonylmethyleneoxyphenyl|- | methylphenyl)-5-fluoro-M2-I3-(M-methylamino)carbonylmethyleneoxyphenin!-2,4- 2,4-pyrimidinediamine (К926851) pyrimidinediamine is obtained as a result of the reaction of M-methyl 3»aminophenoxyacetamide and 2-chloro-M4-(4- cyano-3-methylphenyl)-4-pyrimidinamine. "H NMR (0M50-46): 5 9.7 (5, IN), 9.40 (in, 1H), 8.2 (in, 1), 8.00-7.50 (t, ZN), 7.40-7.00 (t, ZN), 6.50 (Bt, 1H), 4.35 (5, 2NI), 2.60 (z, ZNU, 2.35 (5, ZNU; RH/MS : purity; 9195; MS (m/z): 407 (MN). 7.3.758 5-fluoro-M2-13-(M- Analogous to the preparation of M4-(3,2-difluorophenyl)-5-fluoro-M2-( 34(M-methylamino)carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-M2-|3-(M.

M4-13-(tetrazol-5-yl)phenyl|-2,4-methylamico)carbonylmethyleneoxyphenyl)M4-(3-(tetrazo-5-yl)phenyl|-2,4- pyrimidinediamine (KU26855) pyrimidinedismine is obtained as a result of the reaction M-methyl of 3-aminophenoxyacetamide with 2-chloro-5-fluoro-M4-I3-(1H-tetrazol-5-yl)phenyl|-4-pyrimidinamine, "H NMR (PM5O-46): 5 10.04 (r , 10), 9.65 (b5, 1H), 8.35 (8, 1H), 8.234, 1H,1- 3.9 Gy), 8.004, TN, /- 6.6 Hz), 7.91 ( Ba, 1- 3.6 Hz), 7.77 (4, 18, 1- 8 Hz), 7.57 (6 1H, 3 8.1 Gy), 7.23 (t, 2H), 6.95 (5 1H, 7- 8.4 Hz), 6.46 (vai, TN, P- 1.8 and 8.1 Hz), 4.22 (5, 2NI)), 2.62 (d, ЗН, 4, 2 Gi); LC/MS: purity: 8395; MS (m/z): 436 (MN. 7.3.759 5-fluoro-M2-13-4(M-) Analogously to the preparation of M4-(3,4-lifluorophenyl)- 5-fluoro-M2-|34(M-methylamino)carbonylmethyleneoxyphenyl-|methylamino)carboniummethyleneoxyphenyl|-2,4-pyrimylindiamine, 5-fluoro-M2-13-(0M-

Ma-(M-methylphthalimido-4-yl)-2,4-methylamino)carbonylmethyleneoxyphenyl|-M4-(M-methylphthalimilo-4-yl)-2,4-pyrimidinediamine (K926856). pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-se aminophenoxyacetamide and 2-chloro-5-fluoro-M4-(M-methylphthalimido-4-yl)-4-pyrimidinamine. "H NMR (0M50-46): 5 9.95 (in, 1H), 9.44 (in, 1H), 8.29 (t, 1H), 8.25 o (t, NU, 8.18 (4, IN, 1-1.85 du, 7.88 (Ba, 1H, 3- 4.5 Hyd, 7.75 (F, 1H,4- 6.6 Hz), 7.38 (vv, IN), 7 ...

Gy), 4.28 (5, 2H), 2.99 (in, Z), 2.60 (y, ZN, 3-4.5 Hz LC/MS: purity: 9255; MS (mach 451 (MN. so 7.3.760 ma4-(2,5-dimethoxy-4-chlorophenyl)-5-fluoro- | Similar to the preparation of 44-(3,4-difluorophenyl)-5-fluoro-m2-(3-(M-

M2435-(M-methylamino)carbonidemethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(2,5-dimethoxymethylamico)carbonylmethyleneoxyphenyl)- | 4-chlorophenyl)-5-fluoro-M2-|3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4- b» 2,A-pyrimidinediamine (KU26859) pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide and M4- (2,5-dimethoxy-4-chlorophenyl)-2-chloro-5-fluoro-4-che:pyrimidinamine. "H NMR (SISOU: 6 8.05 (y, IN, 22: 5.4 Hz), 7.29 (5, 1H)), 7.24 (y,

IN, 8 Gy), 7.18 (5.1), 7.02 00 1H,1- 2.1 Gy), 6.92 (ab, IN, 12 1.8 and 8.1 Hu, Ga! 6.83 (44, 1H, 2: 2.4 and 8.4 Gih), 4.29 (5, 2), 3.81 (5, ZNI), 3.59 (5, ZN), 2.81 (5, ZNU;

VZh/MS: purity: 9675; MC (m/z): 460 (MN)-; 462 (МН), со 7.3.761 5-fluoro-Mm2-13-4(М» Analogously to the preparation of IM4-(3,4-difluorophenyl)-5-fluoro-2-13-(M-methylamino)carbonylmethyleneoxyphenyl|- | methylaminocarbonylmethyleneoxyphene li-2,4-pyrimidinediamine, 5-fluoro-M2-/3-4(M-

M4-(3-methoxycarbonyl-5-methypamino)carbonylmethyleneoxyphenyl-M4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-2,4-trifluoromethylphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction M-methyl pyrimidinediamine (KU26862) 3З- aminophenoxyacetamide and 2-chloro-5-fluoro-M4-(3-methoxycarbonyl-5-trifluoromethylphenyl)-4-pyrimidinamine. (n yaMe (0OMBO-a6): 5 9.955, 1), 9.41 (8, 180), 8.57 (in, TAN), 8.33 (5, PN), 8.23 (0, 1Н, 2: With Hz), 7.83 (5 and i, 2H), 7.22 (t, 2H), 7.021, 21 8.7 Gy), 5.48 (1H, 7-24 and 7.5 KG) , 4.27 (z, 2H), 3.80 (5, ZH), 2.60 - s (a, zn, 1-48 Ga); THAT YAM? (YUM5O0-46):-17446; LC/MS: purity: 9495; MS (pu/g): 4294 (Mn. in! » 7.3.762 5-fluoro-M2-(34(M- Analogous to the preparation of M4-(3,4-difluorophenium m 5-fluoro-M2-(3-(M - and methylamino)carbonylmethyleneoxyphenyl|- | methylaminocarbonylmethyleneoxyphenyl-2,4-nyrimidinediamine, 5-fluoro-M2-(3-(M-

M4-(3-(2-pheny-1,3,4-oxadiazol-5-methypamino)carbonylmethyleneoxyphenyl-MA-G/3-(2-phenyl-1,3,4-oxadiazol-5-yl)phenyl-2 ,4-pyrimidinediamine (Н926879) |yl)phenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyanethamide and 2-chloro-5-fluoro-M4-|3-(22-phenyl-1,3 ,4-oxadiazole-5-

Go! yl)phenyl|-4-pyrnimidinamine. LC/MS: purity: 8695; MS (m/z: 512 (MN). 7.3.763 44|34(24(3-chlorophenyl)-1,3,4-oxadiazole- | Similar to the preparation of M4-(3,4-difluorophenyl)-5-fluoro- Mm2-Y3-(M-

Ho) 5-iliphenini-5-fluoro-M2-|34(M-methylamino)carbonylmethyleneoxyphenyl| -2.,4-pyrimidinediamine, M4-|3-(2-43-methylamino)carbonylmethyleneoxyphenyl|- | chlorophenyl)-1,3,4-oxadiazol-5-ylphenyl|-5-fluoro- M2-|3-(M. 2,4-pyrimidineliamine (KU26871) methylamino)carbonylmethyleneoxyphenial|-2,4-pyrimidinediamine is obtained as a result reactions of M-methyl 3-aminophenoxyacetamyl and 2-chloro-5-fluoro-M4-(3-(2-(1-chlorophenyl)»1,3,4-oxadiazol-5-yl)phenyl|-4-pyrimidinamine. РХ /MS: purity: (Se) 42) (F, ko 60 b5

SHISHSH050OISH0O0202020000000011Probemerluvyemtu 7.3.764 5-fluoro-M2-|3-(M- Similar to the preparation of M4-(3,4-difluorophenyl)-5-fluoro-Mm2-I34/M- methylamino)carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenyl)|-2,4-pyrimidinediamine, 5-fluoro-142-(3-(M-

Ma4-(4-trifluoromethoxyphenyl)|-2,4-methylamino)carbonylmethyleneoxyphenyl|-ma4-(4-trifluoromethoxyphenyl-2,4-pyrimidinediamine (K926879) pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-9 aminophenoxyacetamide and 2-chloro- 5-fluoro-M4-(4-trifluoromethoxyphenyl)-4-pyrimidinamine. "H NMR (0M5O0-46): 5 10.05 (rv, 1), 9.74 (Bi, 1H, 5-2 1.5 Hz ), 8.22 (90, 1H, 34.2 Go), 7.99 (Ba, IN, I: 4.5 Hz), 7.86 (t, 2NU, 7.324, 2H, 3: 8.1 Go 7.26 (5, EN), 7.16 (t, 2), 6.58 (t, IN), 4.36 (5, 2H)), 2.65 (Bi, ZNU, RH/MS: purity : 9295; MS (m/z): 452 (MN). 7.3.765 5-fluoro-M2-(3-4(0M- Analogous to the preparation of M4-(3,4-difluorophenyl)-5-dogor- M2-13 -01h- methylamino)carbonylmethyleneoxyphenyl

Ma-(4-trifluoromethylphenyl|-2,4- methylamino)carbonylmethyleneoxyphenyl|- M4-(4-trifluoromethylphenyl|-2,4- pyrimidinediamine (K926880) pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide and 2-chloro-5 -fluoro-M4-(4-trifluoromethylphenyl)-4-pyrimidinamine. "H.NMR (0M50-α6u: 5 10.10 (b5, 1H)), 9.72 (4, IN, 72 1.2 Gy), 8.26 (а, 1Н,21- 4.2 Hz), 8.00 (t, ZNU, 7.654, 2Н, 12 8.1 Hz), 7.31 (5, IN, 7.17 (0, 2Н ,1- 5.4 Hz), 6.59 (t, 1H), 4.36 (5, 2H), 2.62 (y, ЗН, 1- 4.8 Gy); LC/MS: purity: 9295 ;

MS (m/z): 436 (MN). 7.3.766 M4-(4 chloro-3-trifluoromethylphenyl)-5- Similar to the preparation of M4-(3,4-difluorophenyl)-5-fluoro-M2-13-(M-fluoro-m2-(3-(M-methylamino) )carbonylmethyleneoxyphenia)|-2,4-pyrimidinediamine, M4-(4-chloro-3- methylamino)carbonylmethyleneoxyphenyl)- | trifluoromethylphenyl)-5-fluoro-M2-134(/M-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (2920881) 2,4-pyrimidineliamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide and 2-chloro-M4-( 4-chloro-3-trifluoromethylphenyl)-5-fluoro-4-pyrimidinamine. "YAN NMR (0M5O0-46u: 5 10.20 (bv, IN), 9.81 (rz, 1H), 8.28 (d, IN, 1- 3.9 Gy), 8.23 (640, 1H , 3- 8.7 Gm), 8.11 (4.1H,3- 2.4 Go), 7.98 (Ba, 1H, 1: 4.5 Hz), 7.65 (4, 1H, 1 - 8.7 Gy), 7.17 (t, ZN), 6.59 (t, 1H), 4.35 (5, 2NI), 2.63 (0, ZN, 1-42

Hz); LC/MS: purity: 8794; MS (m/z): 470 (MN). 7.3.767 5-fluoro-M24(3-(M- Analogously to the preparation of I44-(3,4-difluorophenyl)-5-fluoro-M2-13-0M- methylamino)zcarbonylmethyleneoxyphenyl)- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidineliamine, 5-fluoro-M2-13-0h-

MA-(quinolin-6-yl)7-2,4-pyrimidinediamine methylamino)carbonylmethyleneoxyphenyl)-MA-(quinolin-b-ip)-2,4-pyrimidinediamine (8926883) is obtained as a result of the reaction of 3M-methyl 3Z-aminophenoxyacetamide and 2-chloro-5-fluoro-ma-(quinolin-b-yl)-4-pyrimidinamine. Н NMR (0М50-д6): 5 10.17 (vv, 16 Ga! 9.83 (5, 1Н), 8.24 (a, 1Н, 1- 4.8 Go), 8.17 (t, IN) , 7.94 (t, 2H), 7.86 (t, IN), 7.39 (d, 1H, 22 9.3 Gu, 7.25 (5, IN), 7.16 (t, 2H) . M442-methoxypyridin-5-yl)-M2- | Similarly to the preparation of M4-(3,4-difluorophenyl)-5-fluoro-M2-134(M-

I-(m-methylamino)carbonylmethyleneoxyphenyl I|-2,4-pyrimidinediamine, 5-fluoro-M4-(2-methylamino)carbonylmethyleneoxyphenyl)- | methoxypyridin-5-yl)-M2-13-(M-methylamino)carbonylmethyleneoxyphenyl)-2,4-"o 2,4-pyrimidinediamine (K9268861) pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide and 2-chloro-5 -fluoro-M4-(2-methoxypyridin-5-yl)-4-pyrimidinamine. "H NMR (OM50-46y; 5 9.36 (B, 1H), 9.19 (5, 1H), 8.59 (0, 1H, 1-b"

With Hz), 8.05 (t, ZN), 7.38 (t, 18), 7.24 (64, 1H, 7-81 Go), 7.08 (i, 1H, 1 8.4 Go) , 6.79 (8, IN, 1- 8.7 Gy), 6.46 (44, IN, 7- 2.4 and 7.8 Gy), 4.34 (5, 210), 3.82 ( 5, ZN), 2.63 "- (d, ZN, 12: 4.5 Hz); LC/MS: purity: 9595; MS (m/3): 399 (MN). 7.3.769 5-fluoro-Mma-12-(2- Analogously to the preparation of M44(3,4-difluorophenyl)-5-fluoro-M2-I13-(M» sem hydroxytylenoxy)pyridin-5-yl|-M2-|3 - | methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, 5-fluoro-M4-(2-4(02- (M- and , hydroxyethyleneoxy)pyridine. 5-12 |-M2-13-47M- and with methylamino) carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained in 2,A-pyrimidinediamine (K927023) as a result of the reaction of M-methyl 3-aminophenoxyacetamide and 2-chloro-5-fluoro-M4-12-2-hydroxyethyleneoxy)pyridine »5-yl|-4-pyrimidinamine. /H NMR (PM5O-46): δ 9.65 (65, 1H), 9.45 (B5, 1H), 8.55 (85, 1H), 8.12 (y, 1H, 1-3, 6 Gy), 7.99 (pi, 2H), 7.28 (t,

INU 719 (t, 28), 7.11 (5, 1H, 2- 8.4 Go), 6.81 (4, IN, 1- 8.7 Sp), 6.52 (t, 2H), 4 .35 (5.2), 4.23 (0.2, 1-5, Hz), 3.691, 2H, 7-45 Go), 2.63 (8, Z, 1-27 Gdu; "

LC/MS: purity: 9595; MS (m/z): 429 (MN. 7.3.770 M4-(2,6-dimethoxypyridin-3-yl)-5-fluoro- | Similar to the preparation of M4-(3,4-difluorophenyl)-5-fluoro-Ich2 -Y3-(M- - with M2-(3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4-(2,6- methylamino)carbonylmethyleneoxyphenyl)- | dimethoxypyridin-3-yl)-5-fluoro- M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl)-p » 2,4-pyrimidinediamine (KU20404) 2,A-pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-aminophenoxyacetamide and 2-chloro-144-(2,6- dimethoxypyridine-3-1H1-5-fluoro-4-pyrimidinamine NR NMR (rmx50-ab): 5 9.05 (a, 1H, 7: 1.8 Hz), 8.62 (5, NR), 8, 01 (4.1H,1- 3.6 Gy), 7.91 (Ba, IN, 3-48 Hz), 7.77 (t, IN), 7.18 (t, 2NU, 6.96 (B , IN, 15 8.1 Gy), 6.40 (0, 2H, 2- 8.1 Hz), 4.29 (5, 2H), 3.86 (5, ЗН), 3.85 (5, ZN), 2.63 (4, ZN, 1-s 4.5 Gy); LC/MS: purity: 8690; MS (m/z): 429 (MG).

THAT! Mmach4-chloro-3-methoxyphenyl)-5-fluoro-M2- | Analogous to the preparation of M4-(3,4-difluorophenyl)-5-fluoro-1m2-13-0M- with 3-(h-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 14-(4-chloro-3-methylamino) carbonylmethyleneoxyphenyl)- | methoxyphenyl)-5-fluoro-M2-13-4(H-methylamino)carbonylmethyleneoxyphenyl|-2,4- 2,4-pyrimidinediamine (KO27042) pyrimidinediamine is obtained as a result of the reaction of M-methyl 3-shk aminophenoxyacetamide and 2-chloro-M4 -(4-chloro-3-methoxyphenyl)-5-fluoro-4-pyrimidinamine. "H NMR (OM5O0-46): 5 9.89 (bv, 1), 9.66 (65, 1H), 8.20 (d, IN, 41- (Ce) (42)

F) ko 60 b5

NI 4.2 Gy"), 7.95 Gbd, IN), 7.48 (t, 2H), 7.33 (4, 1H, 2-91 Gu, 7.26 (65, 18), 7.17 (t , 2NU, 6.57 (6, IN, 22: 7.8 Hz), 4.34 (5, 2H), 3.72 (5, ZN), 7.62 (0, ZN); LC/MS: purity: 9795; MS (m/z: 432 (MIC). 7.3,772 Ma-(3-chloro-4-trifluoromethoxyphenyl)-5- | Solution of 2-chloro-Ma4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro- of 4-pyrimidinamine (1,1 fluoro-M2-(3-hydroxyphenyl)-2,4-equivalents) and 3-hydroxyaniline (1 equivalent) in a hermetically closed pyrimidinediamine flask (K920411) is heated at a temperature of 1002C for 24 hours. The resulting solution is dissolved EOAc, and the solid substance is filtered off, washed with a mixture

EtOAc: n-hexanes (1:1; by volume), dried and analyzed to afford M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinamine . / N

NMR (ST): 8 8.02 (y, 1H, 1- 5.1 Hz), 7.98 (4, 1H, 3 3.0 Hz), 7.72 (46, 1H, 125 3.0 and 9.3 Hz), 7.42 (40, IN, 7 1.2 and 9.0 Hz), 7.22 (, 1H, 7- 8.4 Hz), 6.85 (t, 2H), 6 .73 144, IN, 1-24 and 8.7 Hz); "E NMR "CO500): -16967 and -46027; LC/MS: purity: 70 9790; MS (m/x): 415 (MH). 7.3.773 5-fluoro-M2-(3-tihydroxyphenyl)-M4 -(3-(3- Similar to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3-phenyl-1,3,4-oxadiazol-z-yl)phenylI-2,4- hydroxyphenyl)-2,4-pyrimidinamine, 5-fluoro-IR2-(3-hydroxyphenyl)-M4-|3-(2-phenyl-pyrimidinediamine (К926866) 1,3,4-oxadiazol-5-yl)phenyl|- 2,4-pyrimidinediamine is obtained as a result of the reaction

of 3-hydroxyaniline with 2-chloro-5-fluoro-M4-13-(2-phenyl»1,3,4-oxadiazol-5-yl)phenyl|-4-pyrimidinamine. other Yam? (SFUOYU): 6 7.72 (b5, IN), 7.96 (vd, ЗI), 7.85 (t, 2H), 7.56 (t, 4H), 7.14 (4.1H,7 -2.1 Hz), 6.91 (t, 2H), 6.28 (49, 1H, 72 1.8 and 6.9 Gy);

LC/MS: purity: 8095; MS (m/z): 441 (Mn. 7.3.774 Ma4-(3,4-difluoromethylenedioxyphenyl)-5- Analogous to the preparation of IM4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M24(3-fluoro- M2-(3-tihydroxyphenyl)-2,4-hydroxyphenyl)-2,4-pyrimidinamine, MA-(3,4-difluoromethylenedioxyphenia)-5-fluoro-pyrimidinediamine (K926794) M2-(3-hydroxyphenyl)-2,4 -pyrimidinedismine is obtained as a result of the reaction of 3-hydroxyaniline and 2-chloro-IM4-(3,4-difluoromethylenelioxyphenyl)-5-fluoro-4-pyrimidinamine. LC/MS: purity: 8595; MS (m/z: 377 MN). 7.3l75 5-fluoro-1M2-(3-hydroxyphenyl)-MA-43- Similar to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3-trifluoromethoxyphenyl)-2,4-hydroxyphenyl) -72,4-pyrimylinamine, 5-fluoro-M2-(3-ylproxyphenyl)-M4-(3-pyrimidinediamine (К926885) trifluoromethoxyphenyl)-2,4-pyrimidinedigmine are obtained as a result of the reaction of 3-hydroxyaniline with 2-chloro-5- fluoro-M4-(3-trifluoromethoxyphenyl)-4-lyrimidineamine.

YIN YAM? (0M80-46): 5 9.99 (B5, IN), 9.61 (re, 1H), 8.21 (4, 1H, 7: 6.2 Gi), 7.93 (Ba, 1H, 7 : 7.5 Hz), 7.78 (8, M), 7.43 (1, 1H, 2-8.8 Hz), 7.03 (t, 4H), 6.43 (p, IN);

NMR (M50-06):-16097; PH/LMS: purity: 8590; MS (m/z): 381 (Mn. 7.3.776 Mma4-(2,6-dimethoxypyridine-3-1l)-5-fluoro- Analogous to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro- M2-(3-c 142-(3-hydroxyphenyl)-2,8-hydroxyphenyl)-2,4-pyrimidinamine, M4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-M2-(3- and pyrimidinediamine (926887 hydroxyphenyl)-2,4-pyrimidinediamines are obtained as a result of the reaction of 3-ho)pyrimidinediamine (K926887) tihydroxyaniline and 2-chloro-M4-(2,6-dimethoxypyridin-3-yl)-5-fluoro-4- pyrimidineamine. "H NMR (0M5O-46); 6 9.98 (re, 2H), 8.20 (y, IN, 1-54 Hz), 7.72 ohm, 1H), 6.90 (i, 1H , 7 7.8 Gy), 6.81 (t, 2H), 6.42 (t, 2H), 3.88 (5, ЗН), 3.86 (8, ЗН);

LC/MS: purity: 9495; MS (m/z): 358 (MN). (Te) 73777 5-fluoro-M2-(3-tihydroxyphenyl)-Ma4-(5- Similar to the preparation of M44(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3» methylpyridin-2-yl)- 2.4-pyrimidinediamine / hydroxyphenyl)-2,4-pyrimidinamine, 5-fluoro-M2-(3-hydroxyphenyl)-M4-(5- b (8927017) methylpyridin-2-ip)-2,4-pyrimidinepiamine is obtained as a result of the reaction of 3-hydroxyaniline and 2-chloro-5-fluoro-M4-(5-methylpyridin-2-yl)-4-pyrimidinamine. 8

NMR (DM5O-46): 5 11.39 (65, 1H), 10.59 (65, IN), 8.58 (5, 150, 8.41 (I, 1H, 3- 3 Hz), h- - 8124, 1H, 7-8.7 Hz), 7.82 (6, IN, 1- 8.7 Sp), 7.29 (5, 1), 7.16 (d, 1H, 7: 9 Gy ), 7.05 (B1H, I1- 8.4 Hz), 6.38 (ai, 1H, 1.2 and 6.9 Hz); LC/MS: purity: 9990; MS (m/z): se 312 (UAI.

Zo 7.3.778 M44(6-chloropyridine-3-1l)-5-fluoro-M2-(3- Analogous to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3- he) hydroxyphenyl )-2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinediamine, M4-(b-chloropyridine-3-1l)-5-fluoro-M2-(3- (29279018) tihydroxyphenyl)-7,4-pyrimidinediamine is obtained in as a result of the reaction of 3-hydroxyaniline and 2-chloro-MA-(b-chloropyridin»3-yl)-5-fluoro-d-pyrimidinamine. /N

( 4,

IN, I» 42 Hz), 7.43 (a, 1, 1-- 8.7 Gy), 7.01 (t, ZN), 6.42 (Ba, IN, 1-: 8.4 Ga); "

LC/MS: purity: 9395; MS (m/z): 332 (MN). 7.3.779 5-fluoro-M2-(3-hydroxyphenyl)-h4- Similar to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M24(3- shsh "(quinoliz-b-yl)-2.4 -pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinamine, 5-fluoro-M2-(3-hydroxyphenyl)-M4-(khivolin-6-yl)- c 45927019) 2.4-pyrimidinediamine is obtained as a result of the reaction of 3-hydroxyaniline and 2-chloro -5-fluoro-M4-(quinolin-6-yl)-4-pyrimidinamine. "H NMR (OM5O-46): 5 10.50 (5, 1H), "from 10.14 (5, IN), 8.29 (4, 1H, 32: 4.8 Hz), 8.14 ( y, 1H, 12: 1.8 Hn), 7.96 (8, 1H, 14-: 953 Gy), k 7.83 (ad, 1H, I1-2.4 and 930 Hz), 7.40 (a, 1H, 17- 8.7 Hz), 7.04. 1H, 7-8.1 Hn), 6.93 (t, 2H), 6.52 (t, 2H); LC/MS: purity: 9395; MS (m/z): 365 (MN). 7.3.780 Ма4-(5-chloropyridine-2-1l)-5-fluoro-М2-(3- Analogous to the preparation of М4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-М2-(3-tihydroxyphenyl)- 2,4-pyrimidinediamine hydroxyphenyl)-2,4-pyrimidinamine, M4-(5-chloropyridin-2-1l)-5-fluoro-M2-(3" (se) (8927020) hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-hydroxyaniline with 2-chloro-M4-(5-chloropyridin-2-yl)-5-fluoro-4-pyrimidinamine. /H km NMR (pMI5O-46): 5 10.80 (65, 1H), 9.77 (p5, 1H), 8.45 (Bi, 1H), 8.26 (y, 1H, 1-3, 9

ГИ), 8.15 (4.1Н, 1-8.7 ГН), 7.85 (04, 1Н, I 2.4 and 8.7 Hz), 7.06 (t, ЗН), 6.43 (59, - IN, IN 7.2 Hz); LC/MS: purity: 9795; MS (m/z); 332 (MN). 7.3.781 TI-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro- | Analogous to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3-"se 20 Mo-(3-hydrokeiphenyl)-2,4-.// hydroxyphenyl)-2,4-pyrimidinamine , M4-(4-chloro-2,5-dimethoxyphenyl-5-fluoro-M2-(3-42)

F) ko 60 b5 pyrimidinediamine (5926860) hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-hydroxyaniline and 2-chloro-IM4-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-4-pyrimidinamine . TYA NMR (SOYU О 7.96 (4, 1Н, 1 4.8 Hz), 7.66 (5, 1), 7.13 (5, 1НУ707(Б1Н, 7- 8.7 Hz), 8.86 (t, 2H), 6.57 (49, IN, 1-2 3.2 and 8.1 Go), 3.48 (5, ZN), 3.66 (in, ZNU; "E NMR (SISOU) :-46968. 7.3.782 Ma-4-Hporphenyl)-5-fluoro-M2 42" Similar to preparation. M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3-methoxycarbonylbenzofuran-5-yl) )-2,4-hydroxyphenyl)-2,4-pyrimidinamine, M4-(4-chlorophenyl)-5-fluoro-M2-(2-pyrimidinediamine (5927026) methoxycarbonylbenzofuranez-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction 5-amino-2-methoxycarbonylbenzofuran with 2-chloro-M4-(4-chlorophenyl)-5-fluoro-4-pyrimidinamine. "H NMR (0M5O0-y6):2 10.28 (65, IN), 10.18 (b5, 1H)), 8.25 (y, 1H, 12 4.5

Ро), 7.96 (p, IN), 7.84 (t, IN), 7.67 (t, ЗН), 7.57 (t, 1Н), 7.37 (лд, 7Н, 4-9 ,0 Hz), 3.88 (5,

ZN); LC/MS: purity: 9695; MS (m/z): 413 (MN). 170 7.3.783 M4-(3,4-dichlorophenyl)-5-fluoro-M2-(2- Analogous to the preparation of IM4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3- methoxycarboylbenzofuran-5- yl)-2,4-hydroxyphenyl)-2,4-pyrimidinamine, M4-(3,4-dichlorophenyl)-5-fluoro-M2-(2-pyrimidinediamine (2927027) methoxycarbonylbenzofuran-5-yl)-2,4- Pyrimidinediamine is obtained as a result of the reaction of 5-amino-2-methoxycarbonylbenzofuran with 2-chloro-M4(3-dichlorophenia)-5-fluoro»-4-pyrimidinamine. "H NMR (PM5O0-y6); 5 9.70 (bv, IN), 9.50 (vv, 1), 8.20 (dF, 1H, 32 4.5

Guide), 8.09 (t, TR), 7.80 (t, ZY), 7.62 (t, NI), 7.53 (t, 180, 7.38 (t, 18), 3.88 (5, ZNU;

LC/MS: purity: 9496; ME (m/z): 448 (MN). 7.3.784 5-fluoro-M4-(3-hydroxyphenyl)- M2-(3- Similar to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-2-(3-methoxycarbonyl-5-trifluoromethylphenyl)- | hydroxyphenyl)-2,4-pyrimidinamine, 5-fluoro-M4-(3-hydroxyphenyl)-M2-(3-methoxycarbonyl-5-2,4-pyrimidinediamine (1926863) trifluoromethylphenyl)-2,4-pyrimidinediamine is obtained in as a result of the reaction of 2-chloro-5-fluoro-

M4-(3-hydroxyphenyl)-4-cyrimidineamine with 3-methoxycarbonyl-5-trifluoromethylaniline, /Н

NMR (РМ5О-46): δ 9.98 (5, 1), 9.52 (5, 1H), 8.53 (5, IN), 8.38 (5, 1), 8.20 (4, 1H, 1-4,

Go), 7.69 (85, 1), 7.27 (0, IN, 225 8.5 g), 7.14 (5, 18), 7.05 (0, 1H, 7.8 Hyd), 6, 49 (49, 1H, 121.8 and 8.4 Hz), 3.80 (5, ZNU; LC/MS: purity: 8295; MS (m/z): 423 (MIG). 7.3.785 M2-( 4-chloro-2,5-dimethoxyphenyl)-5-fluoro | Similar to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3-

Ma4-(3-hydroxyphenyl3-2,4- hydroxyphenyl)-2,4-pyrimidinamine, M2-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-M4-(3- tyrimidinediamine (К926857) hydroxyphenyl)- 2.4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidineamine with 4-chloro-2,5-dimethoxyaniline. "H NMR (SOxOR): 5 8.04 (in, 1- 5.4 Gy), 7.46 (5, IN), 7.17 (t, 2H), 7.03 (t, 2), 6 .72 (ab, 1H, 72 1.8 and 7.8 Gsh), 3.85 (5, ZN), 3.52 (5, ZN); LC/MS: purity; 9895; MS (m/z) ; 390 (МН). 7.3.786 M243-bromo-5-trifluorophenyl)-5-fluoro- Similar to the preparation of M4-(3Z-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3»

M4A-(3-hydroxyphenyl)-2,4-hydroxyphenyl)-2,4-pyrimidinamine, M2-(3-bromo-5-trifluorophenyl)-5-fluoro-M4-(3-pyrimidinediamine (2926846) hydroxyphenial)-2,4 -pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-sem 29 pyrimidinediamine (KU26846) hydroxyphenyl)-4-lpyrimidinamine with 3-bromo-5-trifluoromethylaniline. "H NMR (0М5О0-He) avu: 5 9.70 (5, INU, 9.36 (5, 1Н)), 9.34 (5, IН), 8.31 (5, 1), 8.18 (a, 1H, /- 3.5 Hz), 8.02 (5, IN), 7.355, 1, 7.28 (b, IN, 72 7.2 g), 711 g, 1 H, 32-84 Hz) , 7.02 (t, 1H), 6.49 (44, IN, 721.8 and 7.8 Gy); LC/MS: purity: 9495; MS (m/zu: 442 (MN). 7.3.787 5-fluoro-M44(3-tihydroxyphenyl)-M2-I3-11H- | Similar to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3-pyrazol-3-yl)phenyl-2.4 -pyrimidinediamine | hyloxyphenyl)-2,4-pyrimidinamine, 5-fluoro-M4-4(3-hydroxyphenyl)-M2-(3-(1H-pyrazol3- (Te (8926841) yl)phenyl)-2,4-pyrimidinediamine obtained as a result of the reaction 2-chloro-5-fluoro-M4-4(3-

From hydroxyphenyl)-4-pimidinamine with 3-41 H-pyrazole-3-ilyaniline. LC/MS: purity: 8495;

Me 363 (MAG). b" 7.3.788 5-fluoro-M4-(3-tihydroxyphenyl)-M2-13- Similar to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3-(tetrazol-5-yl)phenyl -2,4-tihydroxyphenyl)-2,4-pyrimidinamine, 5-Fluoro-M4-(3-hydroxyphenyl)-m2-(3-(tetrazole-5-h-pyrimidinediamine (H926842)) isophenyl|-2,4-pyrimidinediamine obtained as a result of the reaction of 2-chloro-5-fluoro-M443-hydroxyphenyl)-4-nyrimidineamine with 3-(tetrazol-5-yl)aniline. "H NMR (0M5O0-46): 8 se 10.05 (B5, 1 ), 9.80 (05, 1H3, 8.27 (5, 1H), 8.23 (f, IN, 1-3.3 Hz), 7.86 (8, 1H, 3» 8.1 Hn) 7.65 (0, 1H, 7-5 6.9 Hz), 7.44 (B 1H, 3 7.5 Hz), 7.19 (t, 2H), 6.93 (6 1H, 1- 7.5 Hz), 6.49 (yes, 1H,

From 1-72.4 and V Hz); LC/MS: purity: 8995; MS (m/z): 364 (MN). (ge) 7.3.789 5-fluoro-M4-(3-hydroxyphenyl)-M2-I3-(1,3- | Similar to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3 - oxazol-5-yl)phenyl|-2,4-pyrimidinediamine|hydroxyphenyl)-2,4-lyrimidineamine, 5-fgor-M4-(3-hydroxyphenyl)-M2-(3-41,3-oxazop-5- 15926831) isophenyl|-2,4-pyrimylindiamine is obtained as a result of the reaction of 2-chloro-5-rtor-M4-(3-hydroxyphenyl)-4-pyrimylinamine and 3-(1,3-oxazol-5-yl)aniline. LC/MS: purity: 7695;

Me (m/zu: 364 (MN. « 7.3.790 M2-(3-chloro-4-trifluoromethylphenyl)-5- Analogous to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3 - -in fluoro-M4-(3-hydroxyphenyl)-2,4-hydroxyphenyl)-2,4-pyrimidineamine, M2-(3-chloro-4-trifluoromethylphenyl)-5-fluoro-M4-(3-pyrimidinediamine (8926844) hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-tihydroxyphenyl)-4-pyrimidinamine with 3-chloro-4-trifluoromethoxyaniline. "H NMR (0M50-

GU 46): 5 9.70 (b5, IN), 9.48 (B5, 1H), 8.15 (b4, 18, 3-3.6 Hz), 8.06 (5, 1H), 7.62 ( 44, 1, 12 24 and t and 9.3 Hz), 7.37 (a, 1H, 25 9.0 Go), 7.20 Um, 1NU, 7.11 (t, ZNU, 6.53 (4 , 1H, 1-81 Go);

LC/MS: purity: 9395; MS (m/3y: 414 (MH"). 73 5-fluoro-M4-(3,4-ethylenedioxyphenyl)-M2- Analogous to the preparation of M4-(3-xpor-4-trifluoromethoxy phenyl)-5-fluoro-M24( 3-

3-(tetrazol-5-yl)phenyl|-2,4-tihydroxyphenyl)-2,4-pyrimidinamine, 5-fluoro-M4-(3,4-ethylenedioxyphenyl)-M2-(3-(tetrazol-5-pyrimidinediamine) (K926843) isophenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3,4-(o)ethylenedioxyphenyl)-4-pyrimidinamine with 3-(tetrazol-5-yl)aniline .'H NMR (0M50-a6); 5 9.91 (5, 18), 9.74 (5, 113, 8.29 (5, 1NU, 8.18 (4, 1H, 7- 4.5 Hz ), 7.76 (Ba, 1H, 1-5 1.5 and V Hz), ko 7.644, 18, 1-8.1 Go), 7.46 (6 1H, 7-8.1 Go), 7.29 (p 1H), 7.13 (44, IN, I- 2.4 and 8.7 Gy), -y (Se) 42) ko 60 b5

PYLY PPO o op 6.64 (4.18.3-8.7 Hz), 4.11 (t, 4NU, RH/MS: purity: 910; MS (m/z): 207 (MN). 7.3. 792 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3-(4-methoxy-2-methylphenyl) -2,4- hydroxyphenyl)-2,4-pyrimidinamine, M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(4-methoxy-2-pyrimidinediamine (KO26845) methylphenyl)-2,4-pyrimidinediamine are obtained as a result of the reaction of 2-chloro-3-fluoro-4-(3,4. ethylenedioxyphenyl)-4-pyrimidinamine and 4-methoxy-2-methylaniline. Н АМ? (ОМ5О-46): 5 2 10.30 (655 , IN), 9.10 (b5, IN), 8.22 (b, IN, 7 5.1 Hz), 7.55 (t, 1), 7.15 (t, 1H), 7.07 ( t, IN), 6.92 (t, 2H), 6.82 (4, IN, 3 8.7 Г1ю), 4.22 (5, 4НУ, 3.80 (5, ЗН), 2.15 (5, ЗН); LC/MS: purity: 9495; MS (m/z): 383 (MN). 7.3.793 M2-15-(M-aminocarbonylmethylene-2-oxo- | Similar to the preparation of IM4-(3-chloro-4 -trifluoromethoxyphenyl)-5-fluoro-M2-(3-1,3-oxazol-3(2H)-yl)phenyl|-M4-(3,4-hydroxyphenyl)-2,4-pyrimidinamine, IM2-15-( M-aminocarbonidmethylene-2-oxo-1,3-oxazole» ethylenediox ifenyl)-5-fluoro-2,4-Z(2H)-yl)phenyl|-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained in pyrimidinediamine (2926847) as a result of the reaction of 2- chloro-5-fluoro-M4-(3,4-ethylenedioxyphenia)-4-pyrmylamine and 2-|5-706 amino-d-oxo-1,3-benzoxazol-3(2H)-yl)acetamide. "H NMR (SB5OYU): 5 7.95 (6, 18, 15 84

C), 7.32 (ad, 1H, 72 2.4 and 8.1 Hz), 7.24 (y, 1H, 12 2.4 Hz), 7.19 (t. 2H), 6.95 ( 8, 1H, 122.7 and 9 Hz), 6.80 (d, 1H, 1-9 H), 4.51 (5, 2H), 4.21 (t, 48). 7.3.794 Mm2-i3-(2-ethoxycarbonylmethylene-1,3,4- Similar to the preparation of M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(3-oxadiazol-5-yl)phenyl-5 -fluoro-M4-(3-hydroxyphenia)-2,4-pyrimylamine, M2-|3-(2-ethoxycarbonylmethylene- and 3,4-oxadiazol-5-hydroxyphenyl)-2.4-pyrimidinediamine yl)phenyl-5-fluoro- M4-(3-thihydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction (8926874) of 2-chloro-5-fluoro-M4(3-hydroxyphenyl)-4-pyrimidinamine and 3-(2-ethoxycarbonylmethylene-1,3,4 -oxadiazol-5-yl)aniline. "H YAM? (OM5O-46): 8 9.52 (5, 1), 9.31 (5, NN), 9.28 (5, TV), 8.30 (5, 1H), 8.12 (4, 1H, 72 3.6 Hz), 8.00 (t, 1H), 7.49 (9, 1H, 7- 7.5 Hz), 7.42 (F, 1, 3- 84

Go), 7.30 (t, 1NU, 7.12 (х5, 1Н), 7.03 0, IN, 3- 8.1 Gy), 6.46 (t, IN), 4.21 (5, 2H), 4.15 (in, 2H, 1- 6.9 Hz), 1.19 and, ЗН, Re 7.2 Hz); LC/MS: purity: 9095; MS (m/z): 451 (MN). 7.3.795 M2,M4-bis(3-boronylphenyl)-5-fluoro-2,4- | A mixture of 2,4-dichloro-5-fluoro-pyrimidine (| equivalent) and 3-aminophenylboronic acid (3 pyrimidinediamine (5926836) equivalents) in MeOH is heated in a sealed flask at 100" C for 74 hours. The resulting mixture is cooled to room temperature , acidify 214 HC, and the resulting solid is filtered, washed with water, dried and analyzed, establishing the formation of M2,M4-bis(3-boronylphenyl)-5-fluoro-2,4-pyrimidinediamine. /H

NMR (0M50-46): 5 10.40 (5, 18), 10.07 (5, 1H), 8.25 (y, 8.4 Hz), 7.85 (5, TNK), 7.73 (d, IN, /- 7.5 Hz), 7.63 (56, ZNU, 7.48 (4, 1Н, 76.9 Hz), 7.30 p, NN, /- 84 Hz), 7.12 (618, 1-2.5 Hz);

LC/MS: purity: 8595; MS (m/z: 368 (MN), 7.3.796 M2-(3-boronylphenyl)-M4-(3,4- similar to the preparation of M4-(3-chloro-4-trifluoromethoxyphenia)-5-fluoro-M2-( 3- ethylenedioxyphenyl)-5-fluoro-2,4-tihydroxyphenyl)-2,4-pyrimidinamine, M2-(3-boronylphenyl)-M4-(3,4-ethylenedioxyphenial)-5-pyrimidinediamine (K926837) fluoro-2, 4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4A-4(3,4-sem styrenedioxyphenyl)-4-pyrimidineamine and 33-aminophenylboronic acid. LC/MS:

Ш0Ш0Ш02Ш0520----.1PPpreovoevmevoovomiu (277-00-02 o 7.3.797 (C-ma-(3,4-difluorophenyl)-M2-(2,3- A mixture of an equivalent amount of 2-chloro-M4-(3,4 -difluorophenyl)-5-fluoro-4-pyrimidinamine and dihydro-2-methoxycarbonylbenzofuran-3- | ()-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran in MeOH are shaken in a hermetically sealed ,4-pyrimidinediamine in a closed flask at a temperature of 80" C for 48 hours, then cooled to (K927030) room temperature and dissolved with a mixture of n-hexanes: EYU Ac (i: 1; by volume).

The obtained solid substance is filtered, washed with a mixture of BO Ac: n-hexanes (1: (Ce)

AND; by volume), dried and analyzed, establishing the formation (1-)-M4-(3,4-difluorophenyl)-

M2-(2,3-dihydro-2-methoxycarboniabenzofuran-5-1l)-5-fluoro-2,4-pyrimidonediamine. /H Ge")

NMR (OM5O-i6): 6 10.21 (b, 1H), 9.80 (65, 1), 8.20 (4, 1H, 7-5 4.8 Hz), 7.94 (vv, IN ), 7.43 (t, ZNO, 7.15 (Ly, 1H, A- 8.4 Hn), 6.81 (0, 1H, 72 8, Hz), 5.35 (ai, 1H, 32 6 ,0 and 6.3 Go), 3.69 (8, ZNU, 3.52 (44, 1H, 3- 10.5), 3.22 (84, 1H, 7 9.0 and 6.0 Gnu; LC/MS: purity: 9995; MS h- (m/zu: 417 (MN). 7.3.798 Senma-(4-chlorophenyl)-M2-(2,3-dihydro-2-.- | Analogously to preparation (5 )-M4-(3,4-difluorophenyl)-M2-(2,3-dihydro-2-z.methoxycarbonylbenzofuran-5-yl)-5-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine , ()-М4-(4-chlorophenyl)-М2-

ZB fluoro-2,4-pyrimidinediamine (KU27024) (2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine is obtained in (ee) as a result of the reaction ()-5-amino- 2,3-dihydro-2-methoxycarbonylbenzofuran and 2-chloro-4-(4-chlorophenyl)-5-fluoro-4-pyrimidinamine. "NMR (0M50-46); 8 10.29 (b5, 1H)), 9.89 (bv, 19U 8.21 (d, 1H, 7-5 4.8 Ho), 7.69 (t , 2NI), 7.38 (t, ZNU, 7.13 (Ba, 1H, 1- 8.1 Hz), 6.83 (a, 1H, /- 8.4 Go), 5.36 (44, 18, 3-2 6.3 and 5.7 5), 3.70 (5, ZNO, 3.52 (44, 1H, 4-10.5 Hz), 3.20 (а, 1, 1- 5 ,4 and 5.7 Giu; LC/MS: purity: 9895; MS (ma): 415 (MH). " 7.3.799 (In M4-(3,4-dichlorophenyl)-M24(2,3- ()-M44(3,4-difluorophenyl)-m2-(2,3-dihydro-2-dihydro-2-methoxycarbonylenzofuran-5- | methoxycarbonylbenzofuran-3-yl)-5-fluoro-2,4-pyrimidinediamine, ( 3)-M4-(3,4-dichlorophenyl)-yl)-5-fluoro-2,4-pyrimidinediamine M2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4 -pyrimidinediamine - c (5927031) is obtained as a result of the reaction of (3)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran and 2-chloro-M44(3,4-dichlorophenyl)-5-fluoro-4-pyrimidinamine. /"H NMR (0M5O-46): 6 10.13 (65, and IN), 9.70 (in5, IN), 8.21 (4, 1H, 7: 4.8 Gy), 8.04 ( y, IN, 2: 2.4 Gy), 7.68 (t, EN), 7.54 (4, EN, and 2 329.0 Gy), 7.37 (05, 1H), 7.19 ( t, 1H), 6.80 (4, 1H, 3: 8.7 G o), 5.35 (y, 1H, 12 6.6 Hz), 3.69 (5, ZNU, 3.53 (49, IN, 1-- 10.5 and 11.1 Hz), 3.21 (49, 1H, 7" 6.0 Hz); LC/MS: purity: 10095;

MS (m/x): 450 (MH. 7.3.800 (2)AM2-(2,3-dihydro-2-) Analogous to the preparation of ()-44-(3,4-difluorophenia)-M2-(2,3- dihydro-2-methoxycarbonylbenzofuran-5-ia)-Ma-methoxycarbonylbenzofuran-5-12)-5-fluoro-2,4-pyrimidinediamine, (3)-M2-(2,3-dihydro-2- (se) (2.6 -dimethoxypyridin-3-yl)-5-fluoro-2,4-|methoxycarbonylbenzofuran-5-yl)-144-(2,6-dimethoxypyridin-3-yl)-5-fesor-2,4-pyrimidinediamine (K927032) Pyrimyldiamine is obtained as a result of the reaction of ()-5-amino-2,3-dihydro-2-kemethoxycarbonylbenzofuran and 2-chloro-Ma4-(2,6-dimethoxythyridin-3-yl)-5-fluoro-4-

What pyrimidineamine. "H NMR (OM5O-46): 6 10.03 (5, 2), 8.18 (4, IN, 12 4.8 Go), 7.68 (54, 1H, -y (Ce) 42) ko 60 b5

1-81 Hz), 7.27 (B5, IN), 6.98 (va, IN, 1-8.1 Hz), 6.69 (8, 18, 7-87 Gy), b.44(0 , 18, 1-81

Gi), 5.33 (44, 1H, 12 5.7 Hz), 3.88 (in, ZNO), 3.86 (8, ZN), 3.69 (5, Z), 3.42 (44 , 1H, I-: 10.8 and

NO Hz), 3.10 (44, 1H, 2 6.3 and 6.6 Hz); LC/MS: purity: 9995; MS (m/z): 442 (MN). 7.3.801 (9М24(2,3-dihydro-2- Analogous to the preparation of (3)-М4-(3,4-difluorophenyl)-М2-(2,3-dihydro-2-methoxycarbonylenzofuran-5-17)-5- methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, (3-M2-(2,3-dihydro-2-fluoro-ma4-(2-(2- methoxycarbonylbenzofuran-5-yl)-5- fluoro-M4-(2-(2-hydroxyethyleneoxy)pyridin-5-yl|-2,4-hydroxyethyleneoxy)pyridin-5-yl1-5-pyrimidinediamine is restrained as a result of the reaction (1)-5-amino-2,3- dithidro-2-fluoro-2,4-pyrimidinedismin (K927025) of methoxycarbonylbenzofuran and 2-chloro-5-fluoro-IMA-(2-4(2-tihydroxyethyleneoxy)pyridine-5-1l|- 4-pyrimidinamine), "H YAM? (0M50-46): 5 10.10 (b5, 1Н), 9.70 (05, 1Н), 8.46 (t, 1Н)U, 8.13 (DN, zn 48 Gi), 7.92 ( t, NU, 7.41 (b5, IN), 7.12 (Ba, IN, 3- 8.4 Gi), 6.79 (t, 2H), 5.35 (44, IN, 1 5.7 and 6.0 Hz), 4.24 (2H, 12 5.1 Gy), 3.70 (6, 3H), 3.569 (6, 2H, 12 5.1 Gy), 3.52 (44,

IN, 1, Gi), 3.24 (yes, 1H, 1 6.6 Hz); LC/MS: purity: 9295; MS (m/z): 442 (MIG). 7.3.,802 (С9-М2-(2,3-dihydro-2- Analogously to the preparation of (33-М4-(3,4-difluorophenyl)-М2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)) -5- - methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinlyamine, (3-)-M2-(2,3-dihydro-2-fluoro-Ma4-(3Z-trifluorophenyl)-2,4 - methoxycarbonylbenzofuran-5-1l)-5-fluoro-M4-(3-trifluorophenyl)-2,4-pyrimidineliamine pyrimidinediamine (K927028) is obtained as a result of the reaction of ()-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran and 2-chloro-5-fluoro-M4-(3-trifluorophenyl)-4-pyremidinamine, "1 NMR (OM5O0-46): 7 10.32 (b, 1), 9.90 (c5, 1), 8, 23 (4, 1H, 32: 4.8 Gy), 7.80 (64, IN, 1-5 6.9 Gy), 7.73 (05, IN), 743, 1H, 1-8, Hz) , 7.36 (5, IN), 7.16 (t, 2), 6.79 (9, 1H, 22 8.1 Hz), 5.33 (40, 1H, 2" 6.0 and 6, 6 Gy), 3.69 (in, ZN), 3.51 (ad, 18, 1- 10.5 Hn), 3.20 (da, IN, 2- 6.0 Gy); LC/MS: purity : 9895; MS (m/z): 465 (MN. 7.3.803 (-9-MO-(2,3-dihydro-2-) Analogously to the preparation of ()-M4-(3,4-difluorophenyl)-M2-( 2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-M4-methoxycarbonylbenzofuran-5-1l)-5-fluoro- 2,4-pyrimidinediamine, (-)-M2-(2,3-dihydro-2-(3,4-difluoromethylenedioxyphenyl)-5-fluoro- | methoxycarbonylbenzofuran-5-yl)-ych4-(3,4-difluoromethyleneoxyphenyl)-5-fluoro-2,4-2,4-pyrimidinediamine (5927029) pyrimidinediamine is obtained as a result of the reaction of (5)-5-amino-2,3- dihydro-2-methoxycarbonylbenzofuran and 2-chloro-M4-(3,4-difluoromethylenedioxyphenyl)-5-fcor-4-pyrimidinamic. "H NMR (OM50-y6)y: 5 10.36 (p, IN), 9.93 (65, 1H), 8.22 (y, 1H, 1: 4.8

Go), 7.9 (B5, 1, 7.38 (t, ZNU, 7.15 Ba, IN, 1- 8.7 Hz), 6.79 (4, IN, 2- 6.0 Hz), 5.33 (4th,

IN, 1:63 and 6.6 Hz), 3.69 (5, ZN), 3.50 (49, IN, 7- 10.5 and 10.8 Hz), 3.22 (44, 1H, 3 - 6.0 Gy);

LC/MS: purity: 10095; MS (m/z3): 461 (MNU. 7.3.804 (3 M4-(3,4-difluorophenyl). 5-fluoro-M2- Mixture (3.M444(3,4-difluorophenyl)-M2-(2, 3-dihydro-2-methoxycarboylbenzofuran-5-yl)-5-12,3Z-dihydro-2-(M-fluoro-2,4-pyrimidinediamine, methylamine hydrochloride (5 equivalents) 1a methylaminocarbonylbenzofuran-5-yl|-diisopropylethylamine ( 5 equivalents) in MEOH is shaken in a sealed flask with 2,4-pyrimidinedismine (5927035) for 24 hours at a temperature of 807 C. The resulting solution is dissolved in water, and the precipitate is filtered, washed with water, dried and analyzed, establishing the formation of (7)- M4-(3,4-Diphorphenyl)-5-fluoro-M2-12,3-dihydro-2-(M-He)methylamino)carbonylbenzofuran-5-yl|-2,4-pyrimidinediamine, "B NMR (0M50- 46): 5 9.46 (5, 18), 9.07 (in, NN), 8.05 (t, ЗН), 7.48 (t, 2Н), 7.35 (t, 1Н), 7 .22 (t, 1H)), 6.72 (4, 18, 75 8. Hz), 5.07 (49, 1H, "6.6 and 6.3 Gy), 3.40 (49, 1H) , 3.15 (94, PE), 2.60 (4, ZN, /- 4.5 Hz);

RHLIS: purity: 9895; MS (m/z): 416 (MN). 7.3.805 (in ma(4-chlorophenyl)-M2-(2,3-lihydro-2- | Similar to the preparation of (2)-Ma-(3,4-difluorophenyl)-5-fluoro-M2-(2- (M-(M-methylamino)carbonylbenzofuran-5-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl)-2,4-pyrimidinliamine, (3-M4-4-(se)yl| 5-fluoro-2 ,4-pyrimidinediamine chlorophenyl)-M2-H2,3-dihydro-2-(1M-methylamino)carbonylbenzofuran-5-yl|-5-fluoro-2,4- (K927036) pyrimidinediamine is obtained as a result of the reaction of methylamine hydrochloride and () -M4-(4-(e») chlorophenyl)-M2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine. "H NMR (0M50-46): 5 9.40 (5, 1H), 9.02 (5, 1H), 8.05 (t, 2), 7.84 (44, 7H, 1-27 and 9.3 Hz), 7.51 (vv , 15), 7.32 (60, 7H, 1- 8.7 Hz), 7.23 (64, 1H, 2- 8.7 Hz), 6.72 (4, h

IN, 1- 8.7 Ha), 5.07 (ai, 1H, 1- 6.0 and 6.3 Hz), 3.39 (44, 180), 3.17 (ad, NN), 2, 60 (y, ZN, 754.8

Gi); LC/MS: purity: 9990; MS (m/z33: 414 (MH). sem 7.3.806 (buma-(3,4-dichlorophenyl)-M2-12,3- Analogous to the preparation of (7)- M4-(3,4-difluorophenyl)-5- fluoro-M2-12-(M-dihydro-24(M-methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl|-2,4-pyrimidinediamive, (3-M4-(3,4- methylamino)carbonylboenzofuran -5-yl|- dichlorophenia)-M2-(2,3-dihydro-240M-methylamino)carbonylbenzofuran-5-yl1-5-fluoro-2,4-5-fluoro-2,4-pyrimidinediamine (K927037) pyrimidinediamine is obtained as a result of the reaction of methylamine hydrochloride and (7)3-AM4-(3,4-dichlorophenia)-M2-(2,3-dihydro-2-methoxycarbonylenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine. Pits (0M50-46): 6 9.52 (5, 1H)U, 9.09 (5, 1H)), 8.08 (t, ЗИ), 7.76 (Ba, 1H, 429.3 Hz), 7.504 , 18, 7- 9.0 Hn), 7.43 (B5, 1H), 7.24 (ra, IN, 2- 8.7 Hz), 6.73 (4, 1H, 3- 8.1 Gy), 5.07 (49, 1H, 2- 6.3 and 6.6 Ha), 3.39 (40, IN, 1-- 10.5 Hz), 3.15 (490, IN I- 6.3 Hyd , " 2.60 (a, ZM, 1-4.8 Hz), LC/MS: purity: 9995; MIS (m/z): 450 (MN). 7.3.807 (D-M4-(2.6 -dimethoxypyridine-3-id)-M2- Analogous to the preparation of ()-M4-(3,4-difluorophenyl)-5- fluoro-M2-(2-(M-methylamino)-c H2.3-lihydro-240h»-carbonyl-2,3-dihydrobenzofuran-5-yl1-2,4-pyrimidinediamine, ()-M4-(2,6 -dimethoxypyridine» methylamino)carbonylbenzofuran-5-yl-3-1p)-42-|12,3-dihydro-2-(M-methylamino)carbonylbenzofuran-5-yl|-5-fluoro-2,4- h 5- fluoro-2,4-pyrimidinediamine (К927038) pyrimidinediamine is obtained as a result of the reaction of metypamine hydrochloride and (7)-М4-(2,6-іt dimethoxypyridin-3-yl)-М2-(2,3-dihydro-2-methoxycarbonylboenzofuran -5-yl)-5-fluoro-2,4-pyrimidinediamine. NO (OOP): 6 7.98 (a, 1H, 7e B, Sy), 7.81 (a, IN, /- 3.6 Gi), 7.39 (Ba, IN, 2-2 2, 4 Hz), 7.06 (44, 1H, 2 2.4 and 8.7 Gm), 6.72 (4, 1H, 3-8.1 Hz), 6.31, 1H, l- 8.7

Hyd), 5.07 (44, 1H, 3-6.3 Gy), 3.96 (5, ZN), 3.93 (5, ZN), 3.46 (44, IN, 2 7.8 and 10.5 Gy), 3.19 (40, 1Н, 3 - 5.7 and 6.3 Hz), 2.77 (0, ЗН, 1 - 4.8 Hz); LC/MS: purity: 9895; MS (m/z): 441

Go! (pl. (2) M2-(2,3-dihydro-(- Analogously to the preparation of (7)-M4-(3,4-difluorophenyl)-5-fluoro-M2-(2-(M-

Kz methylamino)carbonylbenzofuran-5-11-methylamino)carbonyl-2,3-dihydrobenzofuran-5-1l|-2,4-pyrimidinediamine, ()-5-fluoro-Ma-(2- -y (Ce) 42) ko 60 b5

5-fluoro-M4-(2-(2- (2-hydroxyethyleneoxy)pyridin-5-yl|-M2-(2-(M-methylamino)carbonyl-2,3- and hydroxyacetylenoxy)pyridin-5-yl)- 2,4-digylrobenzofuran-5-yl1-2,4-pyrmidinediamine is obtained as a result of resection of pyrimidinediamine (KO27039) with methylamine hydrochloride and (7)-M2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-ip)-5- fluoro-ma-(|2-(2-hydroxyethyleneoxy )pyridin-5-ip|-2,4-pyrimhydindiamine. "I YMe (0M5O-db): 5 9.26 (in, 1H), 8.99 (5 . . 7: 8.7 Sy), 5.05 (40, 1H, 7- 6.3 and 6.6 Hz), 4.80 ( 1H), 4.23 (6 2H, A- 5.1 Ty), 3, 69 (06 2H, 1- 5.4 Hz), 3.40 (yes, 1H), 3.15 (40, 18, 2- 6.3 and 9.9 Г), 72.60 (4, ЗН, i- 4.5 Ha); HC/MS: purity: 8692; MS (m/t): 441 (MN). 7.3.809 (9-M2-12,3-dihydro-(Mi- Analogous to the preparation of ()- M4-(3,4-difluorophenyl)-5-fluoro-M2-(2-(M-methydamino)carbonylbenzofuran-5-yl|. methylamico)carbonyl-2,3-dihydrobenzofuran-5-1 11-2,4-pyrimidinediamine, (-M2-(2,3-5-fluoro-M443-trifluoromethoxyphenyl)» dihydro-(M-methylamino)carbonylbenzofuran-5-yl|-5-fluoro-M4-(3-trifluoromethoxyphenyl) )- 2,A-pyrimidinediamine (KO27040) 2,A-pyrimidinediamine is obtained as a result of the reaction of methylamine hydrochloride and ()-M2- (2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-M4- (3-trifluoromethoxyphenyl)-2,4-pyrimilindiamine. LC/MS: purity: 9495; MS (m/z): 464 (MN). 7.3.810 (-m2-H2,3-dihydro-(M. Analogous to the preparation of (7)-M4-(3,4-difluorophenyl)-5-fluoro-M2-12-(04-methylamino)carbonylenzofuran-5-1l |- methylamino)carbonyl-2,3-dihydrobenzofuran-5-yl-2,4-pyrimidinediamine, E)-M2-(2,3-

M443,4-difluoromethyleneoxyphenyl)-5-dihydro-(M-methylamino)carbonylbenzofuran-5-yl|-ma4-(3,4-difluoromethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinethiamine (K927041) fluoro-2,4 -pyrimidinediamine is obtained as a result of the reaction of methylamine hydrochloride and (7)-

M2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-1l)-5-fluoro-M4-(3-trifluoromethoxyphenyl)-2,A-pyrimidinediamine, "H NMR (M5O-96): 4 9.46 (5, 1Н), 9.05 (5, IN), 8.05 (t, ЗН), 7.43 (t, 2). 7.31 (ФБ1Н, 3-87 Gy), 7.23 (Ba, 1Н, 12 7.5 115), 6.70 (6, 1H, 12 9.0 Gy), 5.04 (da, H, 1- 6.6 Gy), 3.40 (d4, 1), 3.14 (40, IN, 7- 5.7 and 6.6 Hn), 2.60 (d, ZN, 7- 3.9 Hz); LC/MS: purity: 9495; MS (m/z): 460 ( МН). 7.3.811 М2-(4-carboxymethyleneoxyphenyl)-МИ- 142-(carboxymethyleneoxyphenyl)-М4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (3,4-styrenedioxyphenyl)-5 -fluoro-2,4- restrained as a result of the reaction of M2-(4-ethoxycarbonylmethyleneoxyphenium)-M443,4-pyrimidinediamine (KU26238) ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine and MON in TNE:H»O at room temperature . "H NMR (0M850-46): 5 8.16 (4, IN, 3" 4.8 Hz), 7.37 (bi, 2H, 1-9 Hz), 7.25 9d0, 1H,1- ЗНх), 7.08 (t, 1Н), 6.83 (t, ЗН), 4.64 (5, 2НИ), 4.23 (5, 4Н); PH/MS: duration of retention: 19.15 min; purity: 10095; MS (m/1): 413 (MN). 7.3.812 M4-(1,4-benzoxazin-b-yl)-5-fluoro-M2-13- | To a solution of M4-(1,4-benzoxazin-b-yl)-5-Ffluoro-M2-13-4(M-(M. methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine (1 equivalent) in MEOH with methylamino)carbonylmethyleneoxyphenyl |- | at a temperature of 0" C, HCl (4M, dioxane, 1.1 equivalents) is added dropwise and 2,4-pyrimidinediamine hydrochloride is shaken for 5 minutes. The resulting solution is dissolved in EOAc, and the solid substance (5920395) is filtered, washed with EtOAc, dried and analyzed , establishing the formation of sem 744(1,4-benzoxazin-b-1l)-5-fluoro-m2-|3-(M-methylamino)carbonylstylenoxyphenyl)-2,4-He) pyrimidinediamine hydrochloride. IN YaMe (YUM50-46) : 5 9.80 (B5, 2H), 8.12 (4, IN, 1-48

Gyu), 7.89 (64, 1H, 1- 4.5 Hz), 7.18 (tu, ЗН)), 8.24 (t, 2), 6.60 (b4, 2H, 1» 8.1 Hz ), 4.36 (in, 2H), 4.10, 2H, 1- 3.9 Hn), 3.27 (, 7, 12 3.9 Gy), 2.62 (4, ЗН, 4-2 : 4.5 Hz); LC/MS: purity: 9895, MS (m/zu: 425 (MN). 7.3.813 Trifluoric acid salt M44(3,4- Analogously to the preparation of M4-(1,4-benzoxazin-b-yl)-5-fluoro -M2-(3-(M- ethylenedioxyphenyl)-5-fluoro-M2-13-(M- methylamino)carbonylethyleneoxyphenyl|-2,4-pyrimidinediamine hydrochloride, salt (Ce) methylamino)carbonylmethyleneoxyphenyl- |trifluoroacetic acid Mi4-(3 ,4-ethylenedioxyphenyl)-5-fluoro-M2-13-0M-2,A4-pyrimidinedismine (K926826) methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of (e") reaction M4-43,4-ethylenedioxyphenyl) -5-fluoro-M24(34(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine and trifluoroacetic acid, "H NAM? (0M50-96): 5 9.40 (b5, 1H), 9.36 (5, 1H), 8.07 (9, 1H, 7: 4.2 Hn), 7.94 (B, 18), h 7.22 (t, 48), 7.105 1H, 15: 7.5 Hyd), 6 .79 (d, TA, 52 8.7 Hz), 6.51 (64, 1Н, 2 7.5 Gy), 4.33 (5, 2Н), 4.21 (05, 4НУ, 2.63 ( 4, ZN, 3.3 Ho), se 7.3.814 5-fluoro-MA-CY H)-indol-b-y lI-M2-(14- Analogous to the preparation of M4-(3,4-styrenedioxyphenyl)-5- fluoro-M2-(3-tihydroxyphenyl)-2,4-

C5 methoxy-3-((M-nyrimidinediamine, 5 ftov-M4-KI H)-indol-b-yl|-M2-(4-methoxy-3-(0M-(ee) methylamino)carbonylmethyleneoxy|phenyl! | methylamino )carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine is obtained as a result of -2,A-pyrimidinediamine (2926752) reaction of 2-chloro-5-fluoro-M4-CYH)indole-b-yl-4-pyrimidinamine and 4-methoxy-3 -Y(M- methylamino) carbonium methylene oxaniline. "H NMR (SIZO): 7.83 (a, IN, I1- 3.6 Hz), 7.73 (4.18, 7- 0.9 Hyd, 7.49 a, 1H, 12 8.1 Hyd ), 7.39 (4, KN, 1- 3.0 Hz), 7.204, 1H, - 3.6 Gy), 7.15 (ab IN, )- 1.8 and 8.1 Hz), 7, 05 (44, 1H, 1-2.1 and 8.7 Hz), 6.81 (4, 1H, 7» 8.7 Gy), 6.43 (y, IN, 1-42 Gy), 4, 09 (5, 2H), 3.81 (5, ZNO, 2.76 (5, ZN); LC/MS: purity: 10095; MS (m/zu: 437 " (mass. 73815 5-fluoro-M4- (3-hydroxy-4-methylphenyl)u | Similar to the preparation of M4-(3,4-styrenedioxyphenyl-5-fluoro-M2-(3-hydroxyphenia)-2,4-8

Mm2-(3-Kh-pyrimidinediamine, 5 fluoro-M4-(3-hydroxy-4-methylphenyl)-M2-13-KM- with methylamino)carbonylmethyleneoxy|phenyl| | methylamino)carbonylmethyleneoxy|phenyl-2,4-pyrimidinediamine and -2,4-pyrimidinediamine (K926753) are obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(2-hydroxy-4-methylphenyl)-4-pyrimidinediamine and 3 -Y(M- and t methylamino)carbonylmethyleneoxy aniline. 1N'YAMe (rM50-a6):5 9.95 (is, IN), 9.83 (p5, 15), 9.38 (05, 1H), 8.17 (4, IN, 2- 4.4 Hz) , 7.97 (y, IN, where 4.8 Hz), 7.24-7.17 (t, 2H), 7.16 (y,

IN, 12 84 i), 71040, 1H, 3-18 and 8.4 Gy), 7.03 (40, IN, 22 2.4 Go), 7.00(4, 1H, 7- 9.0 Hz ), 6.614, 18, 72: 8.7 Gyi), 4.34 (5, NU), 2.63 (0, ZN, 7: 4.5 Hn), 2.08 (5, ZN); LC/MS: purity; 9696; MS (m/z): 398 (Mn. (ee) 7.3.816 3-fluoro-M4-(3-dihydroxyborylphenyl)-M2- | Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2- (3-hydroxyphenyl)»2,4-

From pyrimidinediamine, 5 fluoro-M4-(3-dihydroxyborylphenyl)-M2-|341(M- km methylamino)carbonylmethyleneoxy|phenyl| | methylamino)carbonylmethyleneoxy phenyl-2,4-pyrimidinediamine is obtained as a result of -y (Ce) 42) ko 60 b5

-2,4-pyrimidinediamine (K926754) reaction of 2-chloro-5-fluoro-M4-(3-dihydroxyborylphenyl)-4-pyrimidinamine and 3-10M-methylamino)carbonylmethyleneoxy |aniline. IN YAM (rM5O-a6):5 9.38 (p5, 1 9.22 (B5,

IN), 8.08 (4, 1H, ze 3.6 Gy), 8.06-7.81 (t, 4NU, 7.51 (4, 1H, 1 8.1 Hn), 7.33-7 ,28 (t, ZN), 7.06 1H, 2-81 schi), 6.44 (44, 1H, 7-2.4 and 7.5 Hz), 2.33 (5, 28), 2, 63 (0, ЗН, 75:48 Hz);

LC/MS: purity: 9595; MS (m/z): 412 (MN). 7-3.817 5-fluoro-M4-(3-dihydroxyborylphenyl)-M2- | Similar to the preparation of M44(3,4-ethylenedioxyphenyl)-5-fluoro-Ich2-(3-hydroxypheny)-2,4-(3-hydroxyphenyl)-2,4-pyrimidinediamine pyrimidinediamine, 5-fluoro-M4-(3-dihydroxyborylphenyl )-M2-(3-hydroxyphenyl)-2,4- (K926755) pyrimidiclyamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-dihydroxyborylphenyl)-4-pyrimidinamine and 33-hydroxyaniline. In'yaM" (0ОМ5О0-а6у5 9.68 (65, IN), 9.35 (в, IN), 9.22 (B5, 1), 8.10 (4, 1Н, 72: 3.9 Gy) , 7.88-7.80 (t, 2H), 7.54 (a, IN, 1-72 Gy), 7.31 (1H, 1- 7.2 Hz), 7.08 (0, IN, 1- 8.4 Hz), 6.98-6.93 (t, 2H)U, 5.35 (4, IN, 75 8.4 Hn); BRK/MS: purity: 9695; MS (ma): 341 ( МН. 7.3.818 М2-(3,4 ethylenedioxyphenyl)-5-fluoro-MaА- | Similar to the preparation of Ма-(3,4-ethylenedioxyphenia)-5-fluoro-М2-(3-hydroxyphenyl)-2,4- " (3-hydroxyborylphenyl)-2,4-pyrimidinediamine, M2 (3,4-ethylenedioxyphenyl)-5-fluoro-M4-(3-hydroxyborylphenyl)-2,4-pyrimidinediamine (K926756) pyrimidinediamine is obtained as a result reaction of 2-chloro-5-fluoro-M4-(3-dihydroxyborylphenyl)-2-pyrimidinamine and 3,4-ethylenedioxyaniline. TN NMR (0M8O- "bu b 9.46 (5, 1H), 9.11 (B5, 1H), 8.05 (y, IN, 2: 4.2 Hz), 7.95 (B5, 1H), 7.88 (5, 1H), 7.78 (4,

IN, 2-75 Hz), 7.524, 11-75 Hz), 7.290 1, 4- 7.5 Hz), 7.16 (5, IN), 7.024, 1H, 1-87

Go), 6.65 (4, 1H, 2-8.7 Hn), 3.40 (5, 4H); LC/MS: purity: 9895; MS (m/z): 383 (MN). 7.3.819 5-fluoro-M4-(3-hydroxyphenyl)-M2-(4- Analogously to the preparation of 144-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- methyl- -2 .A-pyrimidinediamine (KU26757) reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine and 4-methyl-3-|( M» methylamino)carbonylmethyleneoxPaniline, IN YAM? (рМ50-а6) :6 9.32 (z, 1H). 9.17 (8, IN), 9.04 (5, 1H), 8.04 (y, 1H, 1-4.2 Hz), 7.76 (4 , 18, 1-5 4.8 Gu), 7.32 cy, 2H, 12 1.6 and 8.1 Hz), 7.13-7.04 (t, ZN), 6.95 (4, 1H , 1-5 8.4 Hz), 6.46 (yes, 1H, 1: 1.8 and 8.4 Hz), 4.31 (5, 2H), 2.65 (y,

ZN, 2-4.8 Gy), 2.14 (5, ZNU; LC/MS: purity: 9995; MS (m/z): 398 (MN). 7.3.820 4-(3,4-ethylenedioxyphenyl) -5-fluoro-MO- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenis)-2,4-(4-methyl-3-CM-pyrimidinediamine, 4 (3, 4-ethylenedioxyphenyl)-5-ftsr-M2-(4-methyl»3-II-methylamino)carbonylmethyleneoxy|phenyl| ) reactions of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4-methyl-3-Y(M-methylamino)carbonylmethyleneoxy aniline. 1Н яЯМе (2М50-а6):6 9.13 (v5, 1Н), 9.05 (5, 1Н), 8.01 (4, IN, 22 4.2 Gy), 7.764, 1Н, 2 4.8 Hz), 7.324, 1H, 1-24 Go), 7.27 (aa, 1H, 2 Ga

I 2.4 and 8.1 i), 7.21 (89, IN, 1 2.4 and 8.7 Hz), 7.13 (0, 1H, 7- 1.8 Hn), 6.95 ( 9, 1H, 72 8.1 Go), 7 o 6.764, 1H, 12 8.7 Hz), 4.28 (5, 2H), 4.20 (5, 4H), 2.65 (9, ЗН, 3-4.8 Hz), 2.15 (5, ZN); R/MS: purity: 9795; MC (m/z)y: 440 (MU. 7.3.821 5-fluoro-M44(3-hydroxy-4-methylphenyl)- Similar to the preparation of I44-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3 -hydroxyphenyl)-2,4- 142-(4-methyl-3-(O-pyrimidinediamine, 5-fluoro-Ma-(3-hydroxy-4-methylphenyl)-M2-|4-methyl-3-Y(M - methylamino)carbonylmethyleneoxy|phenyl| methylphenyl)-4-primylinamine and 4-methyl-3-|(M-(Che)methylamino)carbonylmethyleneoxy|aniline. IN YAM" (OM50-a6):6 10.09 (L5, IN), 9.96 ( c5,

IN), 9.44 (5, IN), 8.16 (y, IN, 2- 4.8 Hz), 7.81 (4, IN, 1-8 Go), 7.13-6.94 ( t, 6H), 4.29 (5, b 2H), 2.644, ЗН, 14.5 Ty), 2.17 (5, ЗН), 2.07 (5, ЗН); VK/MS: purity: 9995; MS (m/z): 412 "We. 7.3.822 5-fluoro-M2,M4-bis4-methyl-3-Y(M- Similar to the preparation of M2,Mm4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 5- -- methylamino) carbonylmethyleneoxy|)phenyl| | fluoro-M2,m4-bis|4-methyl-3-(M-methylamino)carbonylmethyleneoxyIphenyl-2,4- -2,A-pyrimidinediamine (926760) pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4 -mekyl-se 3-KM-methylamino)carbonylmethyleneoxy |(aniline. ТН МАМ (ОМ5О-еб):6 9.30 (in, 1), 9.02 z5 (in, 1H), 8.06 (68, 19 , 3- 3.6 Hz), 7.94 (0, 1H, 7- 4.5 Hz), 7.80 (9, 1H, 14.2 Gy), 7.58 (65, 1H), (ee) 7 ... 4.27 (8, 28), 2.66(a, ZN, 154.2 Gy), 2.63 (4, ZN, 7: 4.2 Gy), 2.18 (5, ZN), 2, 14 (5, ZNU; LC/MS: purity: 10095; MS (m/z): 483 (MN). 7.3.823 5-fluoro-M443-hydroxyphenyl)-M2-43,4,5- | Similar to the preparation of M4 -(3,4-Stylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-trimethoxyphenyl)-2,4-pyrimidinediamine pyrimidinedigmine, C fluoro-M4-4(3-hydroxyphenyl)-M2-( 3,4,5-trimethoxyphenyl)-2,8- (K926761) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenia)-4-pyrimidinamine and 3,4,5-trimethoxyaniline, 1H YaMe (OM 50-a6): 6 9.33 (in, IN), 9.17 (5,

IN), 8.99 (5, 10), 8.06 (0, IN. 2: 3.3 Gy), 7.27 (4, EN, 12 7.5 Go), 7.08-7.02 (t, 4NI), 5.46 (ai, - s IN, /e 1.8 and 7.8 Gy), 3.60 (5, 6), 3.57 (8, ZN); LC/MS: purity; 9995; MS (m/3): 387 (MAH), 7.3.824 m4-(3,4-etiphenedioxyphenyl)-5-fluoro-M2- | Analogous to the preparation of M4-(3,4-ethyphenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- p z" (3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine, M4 (3 ,4-ethylenedioxyphenyl)-5-fluoro-M2-(3,4,5-trimethoxyphenyl)-2,4-p pyrimidinediamine (KU26762) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-Ma-(3,4-ethylenedioxyphenia)- 5-fluoro-4-pyrimilyvamine and 3,4,5-trimethoxyaniline, IN YAM? (0M80-abu 8.08 (I IN, 4.8 Gy), 7.294, IN, 1-24 Gy), 7.15 (44, 1H, 1-3.0 and 9.0 Hn), 6.91 (5, 1H), 6.76 (4, 1H, 2-87

Gy), 4.29 (in, 4H), 3.61 (5, NI), 3.59 (5, ЗН); RH/MS; purity; 9799; MS (m/z); 429 (MN). (se) 7.3.825 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- 13 ,5-dichloro-4-hydroxyphenyl)-2,4- pyrimidinelismin, M4 (3,4-ethylenelioxyphenyl)-5-fluoro-M2-(3,5-lichloro-4-hydroxyphenyl)- pyrimidinediamine (К926763) 2,4 -pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-co fluoro-4-pyrimidinamine and 3,5-dichloro-4-hydroxyaniline. 1H NMR (OM50-v6):6 9.59 (05, -y (Se) 42) ko 60 b5

18), 9.26 (Ba, 2H, 1 7.5 Hz), 8.06 (4, 1H, 7- 3.9 Gy), 7.85 (5, 2H), 7.18-7.13 (t, 28), 6.80 (0, 1H, 725 90 Go), 4.20 (5, 4H); LC/MS: purity: 10095; MS (m/z): 424 (MN). 7.3.826 5-fluoro-M2-(3,5-dichloro-4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-hydroxyphenyl)-m4 -(3-hydroxyphenyl)-2,4- | of pyrimidinediamine, 5 Fluoro-M2-(3,5-dichloro-4-hydroxyphenyl)-M4-(3-hydroxyphenyl)-2,4- pyrimidinediamine (5926890) pyrimidinediamine is restrained as a result of the reaction of 2-chloro-5-fluoro-M4 -(3-hydroxyphenyl)-4-pyrimidinamine and 3,5-dichloro-4-hydroxyaniline. 1 YaMe (rM50-a6):5 9.47 (08, 1H), 9.35 (65, IN), 9.22 (B5, 2H), 8.09 (y, IN, I: 3.6 Go ), 7.70 (5, 2H), 7.31 (ai, IN, 2-1.2 and 9.3 Hn), 7.101, 3- 7.5 Hz), 7.00 (65, TE), 6.48 (44, 1H, 12 1.2 and 6.9 Gy); LC/MS: purity: 9395;

MS (m/z: 382 (MN). 7.3.827 M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2 -(3-hydroxyphenyl)-2,4-

I3-M-pyrimidinediamine, MA (3-chloro-4-methoxyphenyl)-5-fluoro-M2-(3-Y(M-methylamino)carbonylmethyleneoxy|phenyl| G methylamino)carbonylmethyleneoxy|phenyl|-2,4-pyrimidinediamine is obtained as a result of 710 -2,2-pyrimidinediamine (K926891) reaction of 2-chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 3-|(M-methylamino)carbonylmethyleneoxy|aniline. IN YAME (0ОМ50-а6):6 9.85 (re, 1Н)), 9.79 (5, 1Ну 8.17 (4, 1Н, 154.8 Gy), 7.986, 1Н, 2: 3.9 Го ), 7.799, IN, 122.4 Gy), 7.65 (40, IN, 7 3.0 and 9.3 Hz), 7.24-7.09 (t, 4), 6.57 (4, IN, 1- 5.7 Hz), 4.34 (5, 28), 3.82 (in, ZE), 2.62 (y,

ZN, 1 4.8 Gy); LC/MS: purity: 9596; MS "(m/z): 433 (ME). 7.3.828 5-fluoro-M4-(3-fluoro-4-methoxyphenyl)-M2- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-

FROM. pyrimidinediamine, 5 fluoro-Ma-(3-fluoro-4-methoxyphenyl)-M2-(3-HOM-methylamino)carbonylmethyleneoxy|phenyl | methylamino)carbonylmethyleneoxy|phenyl|-2,4-pyrimidineliamine is obtained as a result of -2.A-pyrimidinediamine (K9268923 reaction of 2-chloro-5-fluoro-M4-(3-fluoro-4-methoxyphenyl)-4-pyrimidinamine and 3- KM-methylamino)carbonylmethyleneoxy |aniline, IN 'NMR (OM 5O-a6):6 9.68 (B5, 1), 9.53 (B5,

INU VIZ (4, 1H, 1-42 Hz), 7.97 (4, 1H, 12 4.8 Hz), 7.76 (484, 1H, 15: 2.4 and 13.5 Gy), 7, 47 (4, 19.2-7.5 Hz), 7.27-7.08 (t, 4H), 6.54 (4, 1H, 3: 8.4 tsu, 4.35 (5, 281) , 3.80 (5, ZN), 2.63 (y,

ZN, - 4.8 Ha); LC/MS: purity: 9495; MS (m/z): 416 (MIG). 7.3.829 M443,4-ethylenedioxyphenyl)-5-fluoro-M4- | Analogously to the preparation of 5-fluoro-M4-(3-thihydroxyphenyl)-M2-(4-(3-phenyl-1,2,4-oxadivazole-5-(3-hydroxy-5-methylphenyl)-2,4-yl) methyleneoxyphenia|-2,4-pyrimidineliamine, MA (3,4-ethylenedioxyphenyl)-5-fluoro-Ma4-(3-pyrimidineliamine (K926893) tihydroxy-5-methylphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro -M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, 4-amino-t-cresol hydrochloride, and diisopropylethylamine.

In NMR (OM50-ab): b 9.06 (5, IN), 8.94 (5, IN), 8.11 (5, 1H), 7.86 (4, 1M, 1- 3.9 Gy), 7.21- 7.15 (t, 2), 7.03 (0, 1H, 3- 5.1 Hz), 6.59 (540, 2H, 1- 8.7 Go), 6.52 (49, 1 , 1- 3.0 and 8.1 G i), 4.17 (z, 4H), 2.05 (5, ЗН); LC/MS: purity: 9995; MS (m/z): 369 (MN). si 7.3.830 M443,4-ethylenedioxyphenyl)-5-fluoro-M2- "Similar to the preparation of 5-fluoro-Ma4-(3-hydroxyphenyl)-M2-14-(3-phenyl-1,2, 4-oxadiazole Ge) (3-fluoro-5-trifluoromethylphenia)-2,4-5-yl)methyleneoxyphenyl|-7,4-pyrimidinediamine, M4-(3,4 ethylenedioxyphenyl)-5-fluoro-M2-(3- pyrimidinediamine (5926894) fluorine -5-trifluoromethylphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-

M4433,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3-amino-5-fluorobenzotrifluoride. "H NMR (0M50-45):6 9.75 "5, 1H), 9.32 (4, 14.15 1.2 Hz), 8.13 (4, IN, 1- 3.6 Hm), 7.99 (y,

IN, 12.3 well 777 (8, 1H), 7.21 (0, 1H, 3-24 tsu, 713 (ad, EN, UA 2.1 and 8.7 Hyd), 7.03 (d,

IN, 129.0 Gy), 6.80 (0, 1H, 7: 8.7 Hz), 4.21 (5, 4H); LC/MS: purity: 9795; MS (m/z): 425 (Che) (Mn. 7.3.831 M443,4-ethylenedioxyphenyl)-5-fluoro-M2-1 Similar to the preparation of 5-fluoro-Ma4-(3-hydroxyphenyl)- M2-14443-phenyl - 1,2, 4-oxadiazol- (e») (3-methyl-5-trifluoromethylphenyl)-2,4-5-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M4 (3,4-ethylenedioxyphenyl)-5 -fluoro-M2-(3-pyrimidinediamine (К926895) methyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-

MA-(3,4-Stylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3-amino-5-methylbenzotrifluoroyl. YIN YAM? (0M5O-a6):6 9.57 (Bv, IN), 9.39 (v5, 1H), 8.12 (y, 1H, 7- 3.6 Hn), 7.77 (5, 2NU, 7 ... se (8, ZN); LC/MS: purity: 10092; MS (m/z): 421 (МН.

Zo 7.3.832 M443,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similarly to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-(4-(3-phenyl-1,2,4-oxadiazol-5-he) 45-methoxy-?2-methylphenyl)-2,4- ilumethypneoxyphenyl)|-72,4-pyrimidinediamine, M4 (3,4-ethylenedioxyphenyl)-5-fluoro-M2-(5-pyrimidinediamine (2926896) methoxy-2-methylphenyl)-2,4-pyrimidineliamine is obtained as a result of the reaction of 2- chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 5-methoxy-2-methylaniline, 18 NMR (SOS1zu6 7.91 (65, EN), 7.61 (4, 18.1 21 Ha), 7.17 (9, IN, 1- 3.0 Geo), 7.05 (a, 1H, 1- 9.3

Ha), 7.03 (44, IN, 2- 3.0 and 8.7 Gy), 6.87 (4, IN, I- 8.1 Hz), 6.58-6.60 (t, 2Н ), 6.55 (49, IN, « 1-2 and 8.1 Gy). 4.26 (5. 4H), 3.70 (5, ZNU), 2.22 (5, ZN); IUE NMR (282M Gy, SOSIz):-47450;

I - dov - y

LC/MS: purity: 9995; MS (m/z): 383 (MN). 2 7.3.833 Mma-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-14-(3-pheny-1,2,4-oxaliazop -5-c (2-fluoro-5-methylphenyl)-2,4-yl)methyleneoxyphenyl-2,2-pyrimidinediamine, M4 (3,4-ethylenedioxyphenia)-5-fluoro-2-(2-pyrimidinediamine) (KU26897 ) fluoro-5-methylphenyl)-7,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-Ma-(3,4- z»ethylenedioxyphenyl)-5-fluoro-4-pyrimidinediamine and 2-fluoro-5-methylaniline, " NMR (SOS 8.11 (4, 1, 1: 1.8 and 8.1 Hz), 7.94 (8, 1H, 7- 2.7 Gy), 7.08-6.84 (th, NO), 6.74-6.67 (t, 1H), 6.64-6.59 (t, 1H), 4.27 (5, AN), 2.28 (5, ZN); 19E NMR ( 282M Go, SOSIU:-38659,- 47267; LC/MS: purity: 10095; MS (m/z): 37 (Mn. 7.3.834 443.4 ethylenedioxyphenyl)-5-fluoro-M2- | Analogously to the preparation of 5- fluoro-M4-(3-hydroxyphenyl)"M2-(4-(3-phenyl-1,2,4-oxadiazole-3" (ee) (3,5-difluorophenyl)-2,4-pyrimidinediamine | yl)methyleneoxyphenia |-2,4-pyrimidinediamine, MA (3,4-ethylenedioxyphenyl)-5-fluoro-IR2-(3,5- (8926898) difluorophenyl)-2,4-pyrimidinediamine is obtained as a result reactions of 2-chloro-M4-(3,4-co ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3,5-dichloroaniline. IN YMR (SOS) -y (Se) 42) ko 60 b5

7.54 (a, IN, 1-3.3 Gy), 7.20-7.11 (t, ZNU), 7.02 (z, 1NI), 6.92-5.90 (t, 2H), 6 ... MS (m/z): 375 (MH). 7.3.835 Ma-4(3,4-styrenedioxyphenyl)-5-fluoro-M2- Analogously to the preparation of 5-fluoro-M4-4(3-hydroxyphenyl)-M2- 14-(3-phenyl-1,2,4-oxadiazole-5-(4-trifluoromethylthiophenyl)-2,4-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M4 (3,4-ethylenedioxyphenyl)-5-fluoro -M2-(4-pyrimidinediamine (K926899) trifluoromethylthiophenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4-(trifluoromethylthio)aniline etc

NMR (0M50-abu5 9.73 (8, 1NI), 9.47 (5, 1H), 8.13 (y, IN, 1- 3.6 Hz), 7.79 (4, 2H, 1-90 Gi), 7.51 (0, 2H, 1-90 Hz), 7.28 (0, 1H, 1-21 Hz), 7.12 (40, 1H, 1-24 and 9.0 Hz), 6.83 (0, TN, 1- 8.7 Hn), 4.23 (v, NU, 197 wells (282M Hz OM50-a6u:-12306; PH/MS: purity: 97; MS (m/zu: 439 (MH 7.3.836 Ma-(3-(bezothiazol-2-1l)-4-chlorophenyl|-5-) Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-(4-(3-phenyl-1 ,7, 4-oxadiazol-7170 fluoro-m2-I3-((M-Z-yl)methyleneoxyphenyl/|-2,4-pyrimidinidiamine, MA (3-(benzothiazol-2-yl)-4-chlorophenyl)-5 - methylamino)carbonylmethyleneoxy|phenyl) | fluoro-M2-(3-(M-methylamino)carbonylmethyleneoxy |phenyl)-2,4-pyrimidinediamine restrain -2,4-pyrmidineliamine (K926900) as a result of the reaction IM4-/3-(benzothiazole -2-yl)-4-chlorophenyl)-2-chloro-5-fluoro-4-pyrimidinamine and 3-((M-methylamino)carbonylmethyleneoxy|aniline. NMR (0M50-45):6 9.77 (5) , 185), 9.30 (in, IN), 8.49 (4, 1H, 7- 3.0 Hz), 8.25 (44, 1H, /- 3.0 and 9.0), 8, 21-8.16 (t, 2), 8.06 (6, 1H, 22 7.8 Gihu, 7.92 (0, 1H, 3- 4.8 Hn), 7.63-7, 48 (t, ZNU, 7.30 (1, 1H, 12 1.8 GI), 7.22 (44, IN, 3» 1.8 and 7.5 Ha), 6.95, 1NI, 1- 8.1 Hn), 6.32 dO, 1H, 1-2 1.2 and VA Hz), 4.29 (8, 211), 2.62 (8, IN, 3» 4.8 Hzu; LC/MS: purity: 10090; MS (m/z): 536 (MN). 19 7.3.837 5-fluoro-m2-13-1(05- Analogously to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-Mm2-(4-(3-phenyl-1,2,4-oxadiazole-5- methylamino)carbonylmethyleneoxy|phenyl) |yl)umethyleneoxyphenyl|-2,4-pyrimidinediamine, 5 fluoro-M2-13-(M- -M4-(3-methoxy-4-methylphenia)-2,4- methylamino)carbonylmethyleneoxy |phenyl )-M4-(3-methoxy-4-methylphenyl)-2,4-pyrimidinediamine (KU26902) pnyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4A-(3-methoxy-4-methylphenyl)-4-pyrimidinediamine and 3-methoxy-4-methylaniline. TI NMR (0M5O-a6): 5 9.78 (B, 1H), 9.63 (b, 1), 8.15 (y, IN, 1- 4.5 Gy), 7.94 (y, IN . 5H), 6.57 (4, 1H, 2-81 Hn), 4.31 (5, 7H), 3.66 (5, 3H), 2.62 (4, 1H, 2-48 Hyd), 2 ... -fluoro-M4-(3-hydroxyphenyl)-M2-(4-(3-phenyl-1,2,4-oxadivazole-5-(methoxycarbonyl)-1H)-indole-b-yl|)-2,4- |yl)umethyleneoxyphenyl)|-2,4-pyrimidinediamine, 5 fluoro-M4-(3-hydroxyphenyl)-M2-|2-pyrimylindiamine (К926903) (methoxycarbonyl)(НН)-indole-b-yl)-2,4 -pyrimidinediamine is kept as a result of the reaction of 2-chloro-3-fluoro-Ma-(3-hydroxyphenyl)-4-pyrimidinamine and b-amino-2-(methoxycarbonyl)-(1H)-indole, /H NMR (OM80-46) :6 11.53 (v, 1H), 9.37 (v, 115), 9.18 (4, 2H, 12: 9.9 Gy), 8.08 (4, 1H, 1-3.6 Hz ), 7.96 (vv, 1NU, 7.46 (j, 1H, 4: 9.0 Hz), 7.39-7.35 (t, 2H), 7.16 (6 1H, 3-24 si

Gi), 710-7.04(t, 2NI), 6.48(40, 1H, 7: 2.4 and 7.5 Hn), 3.82 (5, ZN); RH/MIS: purity: 9595: o

MS (m/z): 394 (MN). 7.3.839 3-fluoro-M2-|3-40- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-14-443-phenyl-1,2,4- methylamino)carbonylmethyleneoxypheny) | oxadiazol-5-yl)methyleneoxyphenyl-2,4-pyrimidinediamine. 5-fluoro-M2-13-(0M- -M4-124(methoxycarbonyl)(TH)-indole-b- | methylamino)carbonylmethyleneoxy |phenyl|-M4-(2-(methoxycardonium) 1 H)-indole-b- il|-24- ipl|-2,4-pyrimidinediamine (5926904) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-|(2-(methoxycarbonyl)-(IN indole-b-it|)-4 -pyrimidinamine and 3-Y(M-methylamino)carbonylmethyleneoxy|aniline. in re) by NMR (SOSIS): 6 9.05 (b, 114), 8.35 (5, IN), 8400 (b5, IN), 7.66-7.62 (t, 2H), 7.27-77 (t,

ZN), 7.01-6.90 (t, ZN), 6.64 (94, 1H, I: 2.4 and 8.1 Gy), 0.40 (B5, 1H). 4.49 (5, 2H)), 3.94 (5, ZN), b» 2.75 (a, ZN, 1-5.1 Go); LC/MS: purity: 8695; MS (m/z): A6; KhMN). 7.3.840 ma-I3-C4- Analogously to the preparation of 5-fluoro-M4-(3-tihydroxyphenyl)-M2-14-(3-phenyl-1,2,4-h (ethoxycarbonyl)piperidino|methylphenyl|oxadiazole-5- yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-M4-I3-C4-15-fluoro-m2-I13-((M- (ethoxycarbonyl)piperidino |methyl|phenyl|-M2-(3-(( M- sem methylamino)carbonylmethyleneoxy|pheny- | methylamino)carbonylmethyleneoxy |phenyl-2,4-pyrimidinediamine is obtained as a result of 2,4-pyrimidinediamine (926905) resection of 2-chloro-5-fluoro-M4-(3-C4-(ethoxycarbonyl )piperidino|methylphenyl)-4-so pyrimidineamine and 3-((M-methylamino)carbonylmethylenekeianiline. 1N NMR (OM5O-y6): 933 (5, 1H), 9.20 (5, 1H), 8.09 (4 , 1, 12: 4.2 G i), 7.93 (4, 1H, 1 4.8 P), 7.82 (9, IN, 12 V

Go), 755 (5, 1NU 7.35 (1, 12 4 Gu, 7.29-7.22 (t, 2H), 7.09 (5 IN, 72 8.1 Hyd), 6.96 (y ,

IN, and 7.8 Hz), 6.47 (44, IN, 1- 2.4 and 8.1 Gy), 4.32 (5, 2NU, 4.02 (а, 2Н, 1: 6.9 Gy), 3.39 (v, 2H), 2.73 (a, 2H 11 Gy), 2.63 (4, ZA, 7- 4.5 Hz), 2.30-2.20 (t, 1H), 1.94 0, 2H, 1 I t), 1.74 (0, 2H, 3-9.9 Hz), 1.60-1.50 (t, ZNU, 1.14 (, ZA, P- 6 .9 Gy); RH/MS: purity: 9995; "

MS (bellows); ZM SN). 7.3.841 M2-13-(ethoxycarbonyl-I, 1- Analogous to the preparation of 5-fluoro-M4-(3-tihydroxyphenyl)-M2-144(3-phenyl-1,2,4-oxadiazole-5-- with dimethylmethyleneoxy) phenylI-5-fluoro-IIMa4.yl)methyleneoxyphenyl-2,4-pyrimidinediamine, M2-I3-(ethoxycarbonyl-1.(3-tihydroxyphenyl)-2,4-pyrimidinediamine dimethylmethyleneoxyphenyl-5-fluoro-ma4-(3-hydroxyphenyl )-2,4-pyrimidinediamine is obtained h (K926906) as a result of the reaction of 2-chloro-5-fluoro-Ma4-(3-hydroxyphenyl)-4-pyrimidinamine and 3- and t(ethoxycarbon-I,I-dimethylmethyleneoxy aniline. TN NMR (SIZO): 6 7.91 (4, 1Н, 1-4,8

Ty), 7.20-7.03 (t, 6H), 6.67 (4, 1H, 75 21 and 7.5 Gy), 6.57-6.53 (t, 18), 4.19 ( a, 2H, 4- 6.9

Hn). 1.53 (5, 6H), 1.20 (5, ZH, 1-6.9 Hn); I9E NMR (282M Gy, STOY): "46120; LC/MS: purity: 9195, MS (m/z): 42iMH'). o 7.3.842 M2-3-(ethoxycarbonyl-I.1- Analogously to the preparation of 5-fluoro-M4-(33-tihydroxyphenyl)-h2-14-(3-phenyl-1,2,4-oxaliazole-5"dimethylmethyleneoxy) phenyl|-M4-3,4-n)methyleneoxyphenyl|-2.4-pyrimidinediamine, M2-|3-(hetoxycarbonyl-1,1- ethylenedioxyphenyl)-5-fluoro-2,4-dimethylmethyleneoxy)phenyl)M4-(3 . 60 b5 of pyrimidineamine and 3-(ethoxycarbonyl-1,1-dimethylmethyleneoxy aniline. IN NMR (re): 5 7.924, 1H, 1- 3.0 Hz), 7.21-7.08 (pi, 4H), 7, 00 (49, 1, 2-24 n 8.4 Gy), 6.93 (b5, IN, 6.86 (4, IN, 22 8.7 Hz), 6.99 (4, 1Н, 1- 2 ,4 Hz), 6.45 (da, 1H, 1--1.2, 1.2, and 7.8 Gy), 4.27 (in, ЗН), 4.23 (9. 2H, 1- 6.9 Hz), 1.60 (5, EN), 1.23 (i, ZN, 1» 6.9 Hz); ISE NMR (282M Hz, SOS: - 47216; LC/MS: purity: 8592; MS (m/z): 4694 МН). 7.3.843 M2-I3-(ethoxycarbonyl-1,1- Analogously to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-(4-(3-pheny-1, 2,4-oxadiazole 5" dimethylmethyleneoxy)phenyl|-5-fluoro-h4-nl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M2-/3-(ethoxycarbon-1,1-(3-hydroxy-4-methylphenyl)-2,4- dimethylmethyleneoxy) phenyl|-5-fluoro-144-(3-hydroxy-4-methylphenyl)-2,4-pyrimidinediamine pyrimidinediamine (K926908) is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(2-hydroxy-4-methylphenyl) )-4-pyrimidinamine and 3-(ethoxycarbonyl-I, 1-dimethylmethyleneoxy aniline. IN YAMe «с0С13у: 8 7.86 (b5, 1), 7.80 (65, 1NU, 7.53 (5, 1Н), 7.16-6.86 (t, 41), 6.54 (4 , 2H, 1: 7.5 C), 4.21 (a, 2H, 16.9 Hz), 3.48 (c, 2H)), 2.20 (5, ZNU, 1.60 (5, 61 ), 1.22 (i, ZN, 22 6.9 Hyd; 19E NMR (282M

You, SOSIz): "46808; LC/MS: purity: 9695; MS (m/z); 4cmMy. 7.3.844 M2-13-(ethoxycarbonyl-1,1- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-14-(3-phenyl-1,2,4-oxadiazole-5-dimethylmethyleneoxy)phenyl |-5-fluoro-M4-|yl)umethyleneoxyphenyl|-2,4-pyrimidinediamine, IM2-13-(ethoxycarbonyl-1,1.

TI H)-indol-b-yl)-2,4-pyrimidinedigmine dimethylmethyleneoxy)phenyl |-5-fluoro-M4A-K1 H)-indole-b-yl|-2,4-pyrimidinediamine is obtained in (K926909) as a result of the reaction 2-chloro-5-fluoro-Ma-KI1H)indole-b-yl|-4-pyrimidinamine and 3-"stoxycarbonyl-1, 1"dimethylmethyleneoxy aniline. YIN YAM? (SOSIZ): 6 9.43 (65, 10), 8.64 (5,

NU, 7.92(4.1H, 22 3.6 Hn), 7.66 (1, IN, 22 2.4 Go), 7.54 (4, IN, 7: 8.4 Gy), 7, 44 (5, 1H), 7.19 (BIN, I-3.0 Go), 7.154, 1H, 3-8, Hz), 6.96 (4, 1H, 2- 3.0 Go), 6, 89 (44, 1H, 275 1.8 and 7.5

Go) 6.77 (4, 1H,3- 1.8 m 8.1 Go), 6.52 (44, 1H, 1- 1.8 and 7.5 Hz), 6.49-6.46 (t, 1H) , 4.32 (4, 2H, 1-72 Hz), 1.57 (8, 6H), 1.31 (5 ZH, 15 7.2 Hz); 192 YM (282M Gy, SOSIZ) in: -47190;

LC/MS: purity: 9395; MS (m/3): 4504MH- 7.3.845 5-fluoro-Ma-(3-hydroxyphenyl)-M2-13-Y0M- | Similarly to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-14-(3-phenyl-1,2,4-oxadiazole5-methylamino)carbeonyl-1,1-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-M4-(3-hydroxyphenyl)-M2-|3-((0M» dimethylmethyleneoxy Ifenyl|-2,4-methylamino)carbonyl-1,1-dimethylmethyleneoxy |phenyl-2,4-pyrimidinediamine is obtained in pyrimidinediamine ( K926913) as a result of the reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidine and 3-(M-methylamino)carbonyl-I, I-dimethylmethyleneoxy)aniline. IN YAM (rM50-ar): 5 9.35 (5, 1H), 9.70 (5, 1H), 9.17 (5, 167), 8.07 (4, IN, 3- 3.3 Gb ), 7.93 (4, IN, 2-3.9 Hz), 7.40-7.29 (t,

ZNO, 7.13-7.02 (t, ZNU), 6.47 (4, IN, 4-7.5 Hz), 6.334, IN, 12 7.5 Gy), 2.60 (5, ZN) , 1.37 (in, 6H); LC/MS: purity: 9755; MS (m/z): 4120 МН. ch 7.3.846 3-fluoro-M4-Y1,2,3.4-tetrahydroisoquin-7- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-H4-(3-phenyl-1,2,4-oxadiazole -5- vapl shtia - - y - oyl)-M2-13-4|0m-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-M4-(1,2,3,4-tetrahydroisoquin- 7-yl)-M2-methylamino)carbonylmethyleneoxy|pheny) | (3-C(M-methylamino)carbonylmethyleneoxy|phenyl|-2,4-pyrimidinediamine is obtained in -2.A-pyrimidinediamine (K926914) as a result of the reaction of 2-chloro-5-fluoro-MA-(2-(1-butoxycarbonyl) -1,2,3,4-tetrahydroisoquinoline-7-methyl-4-pyrimidinamine and 3-((Mi-methylamino)carboniamethyleneoxy|aniline. 1H NAM? (pM50-a6): 6 7.90 (y, 1H, 7: 3.3 Hz), 7.47 (4, 1H, 72 2.4 Hz), 7.42-7.37 (t, 2H), 7.16 0 1H, 1-84 Hz and 7.10-7, 04 (t, 2H), 6.50 (ad, 1H, 3- 1,2,2,4, and 8.1 Gy), 4.26 (5, 2NI), 3.93 (v, 2H), (Ce) 3.12 (6B2H, 3-6.3 Hn), 2.84-2.76 (t, 5H), 19E NM? (282M Hz, COzOI3): -47489; LC/MS: purity: 8795; MS (m/z): 423(MN. (e") 7.3.847 M-(3,4 ethylenedioxyphenyl)-5-fluoro-M2- | Analogous to the preparation of 5-fluoro-х4-(3-hydroxyphenyl)- M2-(4-(3-phenyl-1,2,4-oxadiazole-5-

I3-KM-methylamino)carbonyl-1,1-yl)methyleneoxyphenyl)|-2,4-pyrimidineliamine, M4-(3,4-ethylenedioxyphenyl)-5-fluoro- M2-(3-Y(M- or dimethylmethyleneoxy| phenyl|-2,4-methylamino)carbonyl-1,1-dimethylmethyleneoxy |phenyl-2,4-pyrimidinediamine is obtained in pyrimidinediamine (KU26915) as a result of the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro- 4-pyrimidinamine and 3-(M-urea methylamino)carbonyl-1,1-dimethylmethyleneoxy aniline. 1n NAM (STANDING): 5 7.26 (6 1H, 1-7.5 g), 719(4.1H,2 - 93 Hz), 7.13 (6, IN, 7 2.4 Gy), 7.06 (44, 1H, 1-2.4 and 8.7 Gy), 7.04-

From 7.03 (t, IN), 6.83 (4, 1H, 7- 9.0 Hours, 6.75 (4. NN, 1-72 Hz), 4.25 (z, 4NU, 2.76 (5, KhNU, 1.43 (z, ge)

WELL; LC/MS: purity: 9795; MS (m/3)y: A5A(IMN). 7.3.848 5-fluoro-M4-(3-1(M- Mixture of 5-fluoro-Ma-(3-hydroxyphenyl)-M2-|3-(M-methylamino)carbonyl methyleneoxyphenyl|- allylamino)carbonyloxy|phenyl)- M2-(3- 2.4 pyrimidinediamine (20 mg, 0.052 mmol), allyl isocyanate (13 mg, 0.16 mmol), and 2-

Sh-(M,M-dimethylamino)pnyridine (18 mg, 0.15 mmol) in anhydrous TNE (1 ml) is heated with methylamino)carbonylmethyleneoxy|pheny) | at 602 in a sealed flask for two days. The reaction mixture "-2,A-pyrimylindiamine (KU26917) is dissolved in ethyl acetate, washed with 1M HCl and brine. As a result of evaporation, an oily precipitate is obtained, which is purified by preparative TLC (595 g methanol/dichloromethane) with the formation of 5-fluoro-4-Y3-((M-allylamino)carbonyloxy|phenyl)-M2- with 13-K(MCh-methylamico )carbonylmethyleneoxyphenium|-2,4-pyrimidinediamine. IN'NMR (Stor): 57934, 1H,1- 3.6 H 0), 7.62-7.55 (t, 2H), 7.32 (in, IN), 7.30 (i, IN, 125 8.1 Gy), 7.19-7.15 (t, n z» 2H), 6.82 (4, 1H, /e 24 and 8.1 Hz), 6.61 (t, IN), 5.96-5.82 (t, 1H), 5.24 (440, IN, 1-8 and 16.8 Gy, 5.13 (46, IN, 1-18 and 11.7 Go), 4 ... : 9995; MS (mi): 4680MN"). 7.3.849 5-fluoro-M2-(3-Y0M- Analogous to the preparation of 5-fluoro-M4413-Y(M-allylamino)carbonyloxy|phenyl| m 2-(3- |(0M- methylamino)carbonylmethyleneoxy|phenyl) | methylamino)carbonylmethyleneoxy |phenyl)-2,4-pyrimidinediamine and isopropyl isocyanate, (ee) -M4-13-C((M-isopropylamino)carbonyl-M- | 5-fluorine is formed -M2-13-H(M-methylamino)carbonylmethyleneoxy phenyl|-M4-(3-P(M-isopropylamino)carbonyloxy|phenyl-2,4- | isopropylamino)carbonyl|- M-isopropylamino)carbonyloxy |phenyl|-2.4 -pyrimidinediamine, IN pyrimidinediamine (K926916) NMR (OM 5O-96): 5 9.40 (B5, 1H), 9.27 (B5, 1H), 8.12 (4, 18, 7- 3.6 Gy) , 7.94 (0, EN, 1: 39 ko MY Gi). 7.78 ( 9, IN, 3- 8.7 Hz), 7.64 (4, 1H, 1- 7.5 Gy), 7.46 (5, 1H), 7.36-7.26 (t, ZN), 7, 12 (b -y (Se) 42) ko 60 b5

TN, 1- VY go), 681-624, 1), 6,474, 1, Zoya and Vy gz), 54544, IN, 1-39 g), 436 (5, 2H)), 3,65-3,55 (t, 2Н), 3.14 (5, 2НИ), 2.63 (4, ЗН, 1- 3.9 Hz) 1.10 (3, 6Н, 1- 7.2 Н), 0.97 (4.6Н, 1-6.6 Gy). 7.3.850 m4-I3-4(m- Analogously to the preparation of 5-fluoro-M4-(3-|(M-allylamino)carbonyloxy|phenyl|-M2-(3-I0M- (ethoxycarbonylmethyl)aminocarbonyl | methylamino)carbonylmethyleneoxy|phenyl |-2,4-pyrimidinediamine and ethyl isocyanatoacetate, si|phenyl)|-5-fluoro-M2-|3-1(M- is formed M4-13-PEM-(ethoxycarbonylmethyl)amino|carbonyloxy Iphenyl)-5-fluoro- M2-|3- methylamino)carbonylmethyleneoxy|phenyl) ((m-methnamino)carbonylmethyleneoxy|phenyl|-2,4-pyrimidinediamia. 1H NMR (BY ITSELF): 5 -7,4-pyrimidinediamine (K9269158) 7.944, IN, 7: 3, 3 GI, 7.69 (i, IN, 72 1.8 Go), 7.56 (048, IN, 151.2, 1.2, i 8.1 Gy), 7.35 (t,

IN), 7.31 (B1H,2- 8.1 g), 7.184, 1H,37- 2.6 Hn), 7.174, 1H, 7- 1.2 Gy), 6.84 (40, IN, I - 2.4 and 8.1 Hz), 6.63-6.58 St, 1H), 4.42 (5, 2H), 4.20 (4, H, 1: 7.2 Hz), 3, 93 (5, 7NU, 2.80 (5,

ZNU, 1.27 (b, ЗН, 1-7.2 Hz); 19E NMR (282M Gy, XYZOY): -47371; LC/MS: purity: 8995;

MS (m/z: 513(MN. 7.3.851 44-I3-((5- Analogous to the preparation of 5-fluoro-M4-(3-((M-allylamino)carbonyloxy |pheny|-M2-(3-(( 0M- (ethylamino)carbonyloxy|phenyl-5-fluoro- | methylamino)carbonylmethyleneoxy |phenyl |-2,4-pyrimidinediamine and ethyl isocyanate, m2413-KM-Й І is formed М4-|3-І(M-(ethylamino)carbonyloxy |phenyl|-5-fluoro-M2-13-10M- methylamino)carbonylmethyleneoxyphenyl | methylamino)carbonylmethyleneoxy phenyl|-2,4-pyrimidinediamine. EN NMR (SP;»OB: 5 7.94 -2,4-pyrimidinediamine (K926919 ) (a, 1, 72 3.3 Gy), 6.84-6.79 (t, 2H), 7.61-7.55 (t, 2H), 6.62-6.56 (t, 2H ), 7.33-7.27 (t, 18), 7.19-7.17 (t, IN), 4.41 (8, 28), 3.23 (F, 2H, 1: 7.2 Hz), 2.80 (8, ZN), 1.17 (I, ZN, 1- 7.2 schu; 192 NMR (282M Gu, SIMOYU): -47378; RHLIS: purity: 10095; MS (m/3 ): 450MNU. 7.3.852 5-fluoro-M2-(3-Y(M- Analogous to the preparation of 5-fluoro-Ma-(3-hydroxyphenyl)-M2-(4-43-phenyl.-1,2,4 -oxadiazole-5-methylamino)carbonylmethyleneoxy|phenyl |ilumethyleneoxyphenyl-2,4-pyrimidinediamine, 5-fluoro-m2-(3-GOx--Ma-(4-methid-3-trifluoromethnaphenyl) )- methylamino)carbonylmethyleneoxy |phenyl|-M4-(4-methyl-3-trifluoromethylphenyl)-2,4- 2,4-pyrimidinediamine (K926922) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(4 -methyl-3-trifluoromethylphenyl)-4-pyrimidinamine and 3-((M-methylamino)carbonylmethyleneoxy aniline.

In Yam? (OM5O-au: 6 9.79 (rv, 1H)), 9.48 (68, 1H), 8.17 (y, 1H, /« 4.2 Hz), 8.10 (y, YIN 1- x 6.3 GG), 7.96 (4, 1H, 7: 4.8 Hn), 7.89 (8, 1H, 7-21 Gy), 7.38 (y, 1, 1-2 9, 0 Hz), 7.26-7.20 (t, 2НТЛИЙ IN, - 84 Hz), 6.534, 1Н, /- 8.4 Gy), 4.33 (8, 2Н), 2.62 (d, ЗН , uk 8.8 Hz), 2.39 (5, ZNU; LC/MS: purity: 9495; MS (m/z): 450(MIG). 7.3.-853 5-fluoro-ma4-(4-fluoro -3-methylphenyl)-Х2" Similar to the preparation of 5-fluoro-х4-(3-hydroxyphenyl).42-(4-(3-phenyl.1,2,4-oxadiazole-5-

13-((M-yl)methyleneoxyphenyl!-2,4-pyrimidicdiamine, 5-fluoro-M4-(4-fluoro-3-methylphenyl)-M2-13-10M-methylamino)carbonylmethyleneoxy|phenyl| | methylamino)carbonylmethylevoxy)phenyl|-2,4-pyrimidinediamine is obtained as a result of -2,4-pyrimidinedismine (K926923) reaction of 2-chloro-5-fluoro-Ma4-(4-fluoro-3-methylphenyl)-4-pyrimidinamine and 3-HOCH - methylamino)carbonylmethyleneoxy)aniline. IN YAM" (OM50-oru: 5 9.67 (B5, 1), 9.51 (B5, - F -- ( 4 - - -- F --i- --- - - - -- --2 --l- - - ---2-- ----2--5-- - sem

TN), 8.44, 1H, Ia gz), 7954, IN, 724.2 g), 7.604 (44, 1H, 1-27 and 6.9 GYU, 757-750 (t, NU, 7.23- 7.06 (ta, 4H), 6.55 (y, 1H, 1: 7.5 Gy), 4.33 (5, 2H), 2.63 (0, ЗН, 1- 4.8 Gy), 219 Go) (5, ZM); LC/MS: purity: 9495; MS (m/z): A00(mMH). 7.3.554 5-fluoro-m2-13-1(M» Analogously to the preparation of 5-fluoro- M4-(3-hydroxyphenyl)-M2-(4-(3-phenyl-1,2,4-oxadiazole-5-methylamino)carbonylmethyleneoxyphenyl|yl)methyleneoxyphenyl|-2,4-pyrimidineliamine, 5-fluoro-M2-13 -1(М- -М4А-(3-trifluoromethylthiophenyl)-2,4- methylamino)carbonylmethyleneoxy 5-fluoro-M4-(3-(Ce)trifluoromethylthiophenyl)-4-pyrimidinamivu and 3-((M-methylamino)carbonylmethyleneoxy |aniline. INYAMe (0М5О-ав): 6 9.83 (Л5, 1Н), 9, 49 (p5, b 1H), 8.21-8.15 (t, 2H), 8.01 (5, IN), 7.94 (65, 1H), 7.49(6 1H, 15 7.8 Hy), 7,38 (y, 1, 2-78

ГИ), 7.29 (5, 10), 7.220, 1Н, 12 7.5 Hz), 7.14 (5, IN, 35 8.4 Ги), 6.54 (4, IN, 7: 9, 9 Go), 4.34 (in, 7H), 2.62 (4, ЗН, 1- 4.8 Ha); LC/MS: purity: 9895; MS (m/5): 468(MN). h-- 7.3.855 M2-I3,5- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-(44(3-phenyl-1,2,4-oxadiazole-5-si bis(methoxycarbonylmethyleneoxy) phenyl|-|yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M2-|3,5-5-fluoro-M4-(3-hydroxyphenyl)-2,4- bimethoxycarbonylmethyleneoxy)phenyl|-5-fluoro-M4-( 3-hydroxyphenyl)-2,4-pyrimidinediamine

Zo pyrimidinediamine (K925926) is obtained as a result of the reaction of 2-chloro-3-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine and (co) 3,5-bis(methoxycarbonylmethyleneoxy)aniline. TN NMR (STANDING): 6 7.92 (4, IN, 1-42 Hz), 7.20-7.10 (t, ZNU, 6.92 (4, 2H, 1-2.4 Hn), 6 .52 (444, 1, 1-28, 5.8, and 7.5 Hz), 6.12 (4, IN, 1 2.4 Hz), 4.55 (5, 48), 3.77 ( z, 6NU; IZUE NMR (282M Ha, STZOUU: "47342; LC/MS: purity: 9292; MS (m/z): 4730MN. 7.3.856 5-fluoro-M2-Y3-hydroxy-5- Similar to the preparation of M4 -(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- (methoxycarbonylmethyleneoxy)phenyl-pyrimidinediamine, 5-fluoro-M2-I3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl| -M4-(3-ma-(3-hydroxyphenia)-2,4-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-8s pyrimidinediamine (926927) hydroxyphenyl )-4-pyrimidinamine and 3-hydroxy-5-(methoxycarbonylmethyleneoxy aniline, 1H NMR (0M50-av): δ 8.13 (h, 18, I» 4.8 Hz), 7.37-7.33 (t 19, 7.11 F, 1H, 12 8.4 Hyd, "from 7.07-7.05 (t, IN), 6.73-6.65 (t, 2H), 6.51 (44, 1H, 122 ,1 and 8.1 Hz), 5.97 (5, 1), 4.59 (5, 2H), p 3.67 (8, ЗН); RHLMS: purity: 9396; MS (m/z): 49( MN 7.3.857 m243-(0h- Similar to preparation 5 -fluoro-M4-(3-hydroxyphenyl)-M2-14-(3-phenyl-1,2,4-oxadiazole 5-ethylamino)carbonyloxy|phenyl-5-fluoro- | yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M2-I3-((M-ethylamino)carbonyloxy|phenyl|-5-

M443-hydroxyphenyl)-2,4-fluoro-MA-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-(se)pyrimidinediamine (K926928) fluoro-ma-(3-hydroxyphenyl) -4-pyrimidinamine and 3-4(M-ethylamino)carbonyloxyCenilin, etc.

NMR (SOS): 5 7.924, UN, 1 3.0 Hz), 7.67-7.55 (t, 2H), 7.24 (B 1H, 72 7.5 Giv), 7.16 (B, 1H, t 1-7.5 Gy). 7.07-6.98 (t, 2), 6.84-6.79 (iv, 20), 6.67 (t, 2H), 6.60 (4, IN, 327.5 Gy), 5.22 . -y (Se) 42) ko 60 b5

5.14 (t, IN), 3.36-3.27 (t, 7), 2.95 (5, 1), 2.88 (5, IN), 1.20 (4, ZM, 327, 5 Hz; 19E NMR (282M Hz, SOSC): -47012; LC/MS: purity: 9995; MS (m/zu: ZVOMN. 7.3.858 5-fluoro-M2-IZ-hydroxy-5-(0M- Solution 5-fluoro-M2-(3-hydroxy-5-(methoxycarbonylmethyleneoxy)phenyl|-M4-(3-methylamino)carbonylmethyleneoxy|phenyl| |hydroxyphenia)-2,4-pyrimidinediamine (56 mg, 0.13 mmol), methylamine hydrochloride (90 mg, "Ma-(3-hydroxyphenyl)-2,4- 1.3 mmol) and diisopropylethylamine (0.12 ml, 0.70 mmol) in methanol (2 ml) are heated pyrimidinediamine (926929) at a temperature 1002C for 8 hours.The cooled reaction mixture is poured into IM

NOI (20 ml), saturated with Masi, and then extracted with ethyl acetate. Purification by preparative TLC (595 methanol/dichloromethane) resulted in 5-fluoro-M2-13-tihydroxy-5-NM-methylamino)carbonylmethyleneoxy|phenyl)-m4-(3-hydroxyphenyl)-2.4-pyrimidinediamine. 1 Yam? (0M50-46):5 9.29 (y5, 1H), 9.16 (v, 1H), 9.01 (v, 1H), 8.06 (4.1, 4-33 Hz), 7, 87 (y, IN, 3- 4.8 Hz), 7.42 (ad, 1H, 1- 1.5 and 8.1 Gy), 7.13-7.05 (tyu, 2NI), 6.89 - 6.81 (t, 2H), 6.45 (44, 1H, 2- 2.4 and 8.4 Hz), 5.92 (6, 1H, 1- 2.4 Go), 4.28 ( 5, 2H), 3.30 (vv, 70 14), 2.63 (5, ZNU; RH/MS: purity: 9495; MS (m/z): 400 (MN). 7.3,859 1m2-13, 5-bisr(m- Analogously to the preparation of 5-fluoro-M2-|3-hydroxy-5-Y(M- methylamino)carbonylmethyleneoxy|phenyl| | methylamino)carbonylmethyleneoxy |phenyl-M4-(3-hydroxyphenyl)-2,4- pyrimidinediamine, M2 "5-fluoro-M4-(3-hydroxyphenyl)-2,4-13,5-bis KM-methylamino)carbonylmethyleneoxy |phenyl|-5-fluoro-M4-(3-hydroxyphenyl)-2,4 - pyrimidinediamine (2926930) pyrimidinediamine is obtained as a result of the reaction of M2-13,5-bis(methoxycarbonylmethyleneoxy)phenyl-5-fluoro-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine, methylamine hydrochloride, and diisopropylethylamine. /H NMR (SPORU 7.91 (68, IN), 7.25 75 (FIN, 8 Gy), 714-711 (t, 1H), 6.98 (5, 10), 6.97 (5, 1H ), 6.55-6.50 (t, 1NU, 6.26-6.23 (tv, 1H), 4.39 (5, 4H)), 2.81 (5, 6H); 192 YM? ( 282M Hy, SOZOI):-47307; LC/MS: purity: 9996; MS (m/z): 4712: (MN). 7.3.860 5-fluoro-M44(1H)-iyadol-5-yl)-M2 -(3-(0M- | Analogously to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-(4-(3-phenyl-1,2,4-oxadiazole-5-methylamico)carboxylmethyleneoxy | phenyl | yl )methyleneoxyphenyl|-2,4-pyrimidinediamine, 5 fluoro-M4-CI Nu indol-5-yl|-M2-3-CM- -2,4-pyrimidinediamine (K926931) methylamino)carbonylmethyleneoxyphenyl!-2,4-pyrimidinedismine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-CIN)-indol-5-yl|-4-pyrimidinamine and 3-(M-methylamino)carbonylmethyleneoxy|aniline. 1H NMR (pM5O-abub 11.09 (B5, 1H), 9.93 (65, 18), 9.67 (B5, IN), 8.17 (4, 1H,, 22 4.81 Hz), 7 .94-7.82 (t, 2H), 7.37-7.22 (t, 4), 7.13 (65, 1NU LO? 1H, 32 8 Gd), 6.58 (0, IN, 17 ,8 schi), 6.37 (5, 1), 4.32 (5, 2H), 2.61 (y, ZN, 1- 4.2 Hz); LC/MS: purity: 9290; MS (m /iso: 407 (MG). 7.3.861 5-fluoro-M2-(3-hydroxyphenyl)-M4-(I14)" Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-(4-(3 -phenyl-1,2,4-oxadiazol-5-indol-5-yl|-2,4-pyrimidinediamine ilumethyleneoxyphenyl|-2,4-pyrimidinediamine, 5 fluoro-M2-(3-tihydroxyphenyl)-MA-K1 H) -indole (8926932) 5-yl1-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-MA-CIN U inlol-5-yl1-4-pyrimidinamine and 3-hydroxyaniline. IN NMR ( 0М5О-а6):5 11.13 (5, NO), 10.25 si (05, 1Н, 9.87 (б, 1Н), 9.43 (B5, 1Н)), 8.16 (4, IN , 1: 5.1 Gy), 7.89 (4, 1H, 1- 0.09 Go), 7.39- Ge) 7.27 (t, ZNU, 7.03-6.94 (t, 2H ), 6.83 (5, 1H), 6.48 (0.18, 3-7.5 Hz), 6.40 (IN, 1- 2.1 Gy);

LC/MS: purity: 9295; MS (m/z: 336 (MN). 7.3.862 5-fluoro-M4- CY HO-indoya-6-12|-42-|3-((M-) Analogously to the preparation of 5-fluoro-M4-(3- hydroxyphenyl)-M2-144(3-phenyl-1,2,4-oxadiazole-5" methylamino)carbonylphenylI-2,4-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, 5 fluoro-M4-I1H)indole-b -yl)-M2-(3-((M-pyrimidinediamine (K926933) methylamino)carboyl|phenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro- (Che)

3-Fluoro-MA-((1H)indol-b-yl)-4-pyrimidinamine and 3-Y(M-methylamino)carbonyl|aniline. In

NMR(С05О0):6 7.99 (6 1Н, 1-5 1.8 Hz), 7.89 (d, IN, 2-2 3.6 Hz), 7.78-7.76 (t, 18 ), 7.70 (444, Teh!

IN, le 12, 2.4, and 8.4 Hz), 7.50 (4, MA, 1-90 Ge), 7.31 (9, IN, 7-2 and 7.5 Hz), 723- 717 (t, ZN), 6.43 (00, 1H, 1-1.2 and 3.6 Gb), 2.73 (in, ZNU; 192 NMR (282M Hz, SP»OB):-47513;

LC/MS: purity: 9995; MS (m/z): 377 (MN). or 7.3.863 5-fluoro-M44(I1H)-indol-b-yl|-M2-13-4(M- Analogous to the preparation of 5-fluoro-M4-(3-hydroxyphenium)-M2-(4-(3- phenyl-1,2,5-oxadiazo-5-morpholinocarbonia)phenyl-2,4-yl)methyleneoxyphenyl|.2,4-pyrimidinediamine, 5 fluoro-M4-((1H)-indol-b-yl|-M2- /13-(0M-se pyrimidinediamine (5926934) morpholinocarbonyl)phenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-

ZB fluoro-M4-K1H)inlol-b-yl|-4-pyrimidinamine and 3-(M-morpholinocarbonyl)aniline. 1H NMR (ee) (SOI 7.96 (0, IN, 1- 4.8 Gy), 7.73 (1, IN, 2-2.4 Gy), 7.66 (4, IN, 1» 1 ,2 Hn), 7.52 (4, IN, 1-2 8 Gy), 7.49 (ad, IN, 7-0.09, 2.1, and 8.1 Ha), 7.33-7.26 (t, 2H), 7.19 (49, 1H, 3-5 1.8 and 8.7 tsu, 7.12-7.06 (t, 1H), 6.45 (44, 18, 3-: 1.3 Ta 3.0 Gy), 3.62-3.15 (vi, 8); 192 NM? (282M Gu, SRzOYU):-46545; RH/MS: purity: 9195; MS (m/zu: 433 ( MH). 7.3.864 Mm2-I3-CA- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl). M2-(4-(3-phenyl-1,2,4-oxadiazole-5-" (ethoxycarbonyl) piperidino|carbonyl|phe !yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M2 I3-C4-nyl)|-5-fluoro-M4-D11)-indole-b-yl|-2,4- (ethoxy carbonyl) piperidino|carbonylIphenyl|- 5-fluoro-Ma-(( 1NI)-indol-b-yl|-2,4- - pyrimidinediamine (926935) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-CI1NI)indole -b-ily-4-s pyrimidineamine and 3-H4-(ethoxycarbon)piperidinoaniline. IN NMR (SISO):6 7.99 (y,

IN, 1-51 Gy), 7.64-7.58 (tp, 2), 7.52 (4, 1H, 1-87 Go), 7.48 (two, 1, 22 1,2,2, 4, and 8.1 h Gi, 7.34-7.27 (t, 25), 7.19-7.13 (t, 2), 6.46 (y4, 1H, 1- 1.2 and 4 ,2 Hz), 4.40-4.27 (t, 18), and » 4.13 (a, 2H, 3- 6.9 Hn), 3.56-3.41 (t, 1), 2 ,95-2.82 (t, 2H), 2.58-2.47 (t, 1H), 1.98-1.82 (t,

IN), 1.75-7.60 (t, 1), 1.58-1.39 (t, 7), 1.24 (i, ZN, 4-- 6.9 Gy); 1UE NMR (282M Hn,

SIZO)-46101; LC/MS: purity: 9095; MS (m/z); 503 (MN). 7.3.865 5-fluoro-Ma-(3-hydroxyphenyl)-M2-I3-KM- | Similarly to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-(4-(3-phenyl»1,2,4-oxadiazol-5-o methylamino)carbonylphenyl)|-2,4-yl)methyleneoxyphenyl|- 2,4-pyrimidinediamine, 5-fluoro-M4-(3-hydrocoephenide)-M2-I|3-((M-pyrimidineliamine (2926936) methylamino)carbonyl|phenyl-2 4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro- 5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimidinamine and 3-|(M-methylamino)carbonylaniline. Other (Ce) 42) ko 60 b5

NMR (CO 8.01 14, 1H, 1- 5.4 g), 7.84 (0 1H, 1- 1.8 g), 7.68-7.61 t, 2H), 7.45 (i, 1H , I 84 Hz), 7.16-7.03 (t, ZN), 6.68 (4, 1H, 22 1.2 and 8.7 Hz), 2.90 (5, ZNU; РХ/MS: purity: 9579; MS (m/z); 354 (mi 7.3.866 5-fluoro-Mα-(3-hyloxyphenyl)-M2-(3-I(M- | Similar to the preparation of 5-fluoro-M4-(3- tyloxyphenyl)-х2-|4-(3-phenyl-1,2,4-oxadiazole-5" propylamino)carbonyl|phenyl|-2,4-yl)methyleneoxyphenyl|-2,4-pyrimidinidiamine, 5 fluoro-M4- (3-hydroxyphenia)-4 2-(3-10M-pyrimidinidiamine (2926937) propylamico)carbonylphenyl|-2,4-pyrkmylindiamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M44(3-tihydroxyphenyl)-d-pyrimidiamine and 3-|(MCH-propylamino)carbonyl|aniline

NMR (SPOYUUV 8.00 (4, 1NI, 3- 5.4 Hz), 7.84 (5 1H, 1e 1.8 Hz), 7.69-7.59 (t, 2H), 7.44 ( i, 1H, 1-75 g), 7.16-7.05 (t, ZNU, 6.67 (14, 1H, /- 2.4 and 7.2 Pi), 3.34-3.29 ( t, 2H), 1.65-1.56 (t, 2H), 0.96 (i, ZN, 12 7.5 Hz); I9E NMR 4282M Hn, SOzOR): -46049; LC/MS: purity: 9495;

MS (m/z: 382 (MN. 7.3.867 5-fluoro-M4-(3-hydroxyphenia)-1M2-13-(M- Analogously to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-H4- (3-phenia-1,2,4hoxadiazole-5-7170 morpholinocarbonylphenyl|-2,4-yl)methyleneoxyphenyl-2,4-pyrimidinedismine, 5-fluoro-MA-(3-hydroxyphenyl)-M2-Y34(M» pyrimidinediamine ( K926938) morpholinocarbonyl)phenyl-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5"fluoro-im4-(3-hydroxyphenyl)-4-pyrimylamine and 3-(M-morpholivocarbonyl)aniline. etc.

YAMRI (SOSO):6 7.93 (y, 1H, 1-36 Hz), 7.546 IN, 1-8 Hn), 7.62 (aa4.1H, 1-12, 2.4, and 8 Go), 732 NN, 12:84 Hz), 7.19-7.10 (t, 38), 6.96 (d4, 1Н, 1-1.2 and 7.8 Hz), 6.56 (h44,

IN, ze 1.2, 3.0, and 6.9 Hz), 3.78-3.34 (t, 8H); 19E NMR (282M Gy, GHG):-47323; LC/MS: purity: 10095; MS (m/z): 410 (МН 7.3.868 m2-13-(8- Analogously to the preparation of 5-fluoro-ma4-(3-hydroxyphenia)-M2-(14-(3-phenyl-1,2,4- oxadiazode5- (stoxycarbonyl)piperidino|carbonyl|phe|yl)methyleneoxyphenyl-2,4-pyrimidinediamine, 2-I3-((4-nyl!-5-fluoro-M443-hydroxyphenyl)-2,4-(ethoxycarbonyl)pyridino |carbonylphenyl-5-fluoro-M4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (2926939) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-MA-(3-thihydroxyphenyl)-4-pyrimidinediamine and 3- (4-(ethoxycarbonyl)piperidinocarbonylaniline. TN NMR (SizOu6 7.92 (d, 18, 1- 3.6 Hz, 7.82 (5, 1), 7.62 (b, 1H, 1.2 and 8, 4 Hz), 7.30 (0 1H, 1- 8.4 Hz), 7.19-7.09 (t, ZN), 6.93 (4, 1, 3-2: 7.5 Go), 6.55 (8, 1H, 2: 1.2 and 7.5 Hz), 4.43 (xi,

IN, 1-2 12.3 Hz), 4.13 (4, 2Н, 2- 6.9 Hz), 3.7 (Л6, 1Н, 15:11.7 Рв), 3.19-2.92 St, 2), 2.67-2.52 (t, IN), 2.06-1.50 (t, 4NU, 1.24 (i, H, 3» 6.9 Hz); I9E NMR (282M Gu, PAGE); -47299;

LC/MS: purity: 9995; MS (m/z): 480 (MN). 7-3.869 Ma-I3-4- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-14-(3-phenyl-I,2,4-oxadiazole-5-(ethoxycarbonyl)piperidinoi)carbonyl|phe | yl)methyleneoxyphenyl)|-2,4-pyrimidinediamic, M4 /3-1(14-nia|-5-fluoro-M2-(3-hydroxyphenyl)-2,4- (ethoxycarbonyl)piperidino|carbonylphenyl|-5-fluoro -M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine (926940) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-|3-((4- p ethoxycarbonyl)piperidinoicarbonylphenyl-5-fluoro-4-pyrimidinamine and 3- sem 29 of hydroxyaniline. IN NMR (SIZO 7.93 (4, 1H, 1: 3.6 Gy), 7.89 (, IN, - 1.8 Hyd), 7.83 (I, He)

IN, 1- 1.2 and 8.4 Gy), 7.41 (5 1H, 1: 7.8 Gy), 7.11-6.05 (t, 4H), 6.41 (a, IN, 7-5 1.8 and 7.2 g), 4.44 (Ly, 1H, 3-12.9 Gy), 4.10 (9, 2H, 17.2 Hz), 3.73 (Ba, 18 , 7- 12.3 Gy), 3.18-2.98 (t, 2H), 2.67-2.55 (tu, 1H5), 2.05-1.53 (t, 4H), 1, 23 (g, ZN, 72 7.2 Hz); I9E NMR (282M Hz, SIZO. 47483; LC/MS: purity: 9995; MS (m/z): 480 (MH). 7.3.870 4-(3-C4- Analogously to the preparation of 5-fluoro-m4-(3 -tihydroxyphenyl)-M2-14-(3-phenyl-1,2,4-oxadiazole-5- (Che) (ethoxycarbonyl)pteridino|carbonylif | yl)methyleneoxyphenyl)-2,4-pyrimidinediamine, IM4-13-( 4- nil|-5-fluoro-M2-13-((M- (ethoxycarbonyl)piperidino|carbonyl|phenyl|-5-fluoro-M2-I13-HOM- methylamino)carbonylmethyleneoxy|phenyl| | methylamino)carbonylmethyleneoxy Ifenyl|- 2,4-pyrimidinediamine is obtained as a result of (2) -2.A-pyrimidinediamine (2926941) reaction of 2-chloro-MA-|3-(Г4-(ethoxycarbonyl)piperidino|carbonylphenyl)|-5-fluoro-4-pyrimidinamine and 3-H(M-methylamino)carbonylmethyleneoxy aniline. "H NMR (SISO) b chi! 7.95 (4, 1H, 3-2: 3.3 Hz), 7.90 (6 1H, 3- 1.8 Hn), 7.80 (444, 1H, 3- 0.09, 21, 8.1 Gy), 7.39 6, IN, 1-75), 7.316 1H, 251.2 Hz), 7.17- 7.06 (t, ЗН), 6.60-6.54 (t, 1Н), 4.48-4.38 (t, ЗН), 4.10 (а, 2Н, 12 6.9 Hz), 3.78-3.65 (t, IN), 3.17-2.95 (p 2H), 2.79 (5, ЗН), 2.65-2.53 (t, 1H), i. 2 ,01-1.52 (t, 48), 1.22 (i, ZN, 1 6.9 Guide; I9E NMR (282M Hz, SP»OYUU:-47309; LC/MS: purity: 9995; MS (m/z): 551 (MH). he) 7.3,871 Reaction of 3-hydroxyaniline and 2-chloro-5- Similarly preparation of 5-fluoro-Ma-(3-hydroxyphenyl)-M2-14-(3-phenyl-1,2,4-oxadiazol-5-fluoro-M4-(1,2,3,4-tetrahydro-1-yl) )methyleneoxyphenia)|-2,4-pyrimidinediamine, as a result of the reaction of 2-chloro-5-fluoro-MA-hydroxynaphthalene-7-yl)-4- (1,2,3,4-tetrahydro-1-hydroxynaphthalene-7- yl)-4-pyrimidinamine and 3-hydroxyaniline pyrimidine give two products, 2926942 and KU26943. « 7.3.872 MA-(1-ethoxy-1,2,3,4-tetragylronaphthalene- | TN NMR (OM5O-46u:5 9.23 (in, IN), 9.14 (bv, IN), 8, 97 (b5, IN), 8.04 (0, IN, 12 3.6 Go), 7U71 20 7-yl)-5-fluoro-M2-(3-hydroxyphenyl)-24-1 (ab, 18.2 - 3.4 and 7.5 Hz), 7.56 (5, IN), 7.14-6.98 (t, ZN), 6.93 (i, IN, 1-8, Gy), 6.29 ( ra, -o pyrimidinediamine (KU26942) IN, 1-7, g), 4.35 (5, IN), 3.59-3.36 (t, 2H), 2.69-2.60 (t, 2H )), 1.89-1.78 (t, 2H), 1.72- s 1.56 (t, 2H), 1.08 (i, ЗН, 3- 6.9 Hz); LC/MS: purity: 9692; MS (m/z): 395 (MN). ts 7.3.8573 3-fluoro-M4-(3,4-hydronaphthalene-7»yl). IN NMR (0M50-46):5 9.19 (5, NO, 9.01 (5, IN), 8.04 (d, 1H, 2- 3.6 Gy), 7.56-7.46 ( t, 28), i» Sword tidrokoifeniyau va 7.16-7.03 (t, ZN), 6.94 y, 1H, 1- 8.1 Hn), 6.46 (d, IN, 3- 9, 6 Hz), 6.03 (ad, 1H, 1 1.8 and 8.1 pyrimidinediamine (K926943) Hy), 6.09-6.01 (t, NN), 2.69 (y, 2H, 1» 8, 4 Gy), 2.28-2.20 (t, 2Nu; 19E NMR (282M Hz,

ОМ50-а6):-49541; LC/MS: purity: 9895; MS (m/z): 349 (MN). 7.3.874 5-fluoro-M4-(3,4-dihydronaphthalen-7-yl)" Similar to the preparation of 5-fluoro-Ма4-(3-hydroxyphenyl)-М2-14-(3-phenyl-1,2,4- oxadiazol-5-m2-I3-(M-ilumethyleneoxyphenyl|-2,4-pyrimidinediamine, 5-fluoro-m4-4(3,4-dihydronaphthalen-7-yl)-M2-|3- (ee) methylamino)carbonylmethyleneoxy| phenyl| | ((M-methylamino)carbonylmgethyleneoxy |phenyl|-2,4-pyrimidinediamine is obtained as a result of -2,A-pyrimidinediamine (926944) reaction of 2-chloro-5-fluoro-Mm4-41,2,3,4- tetrahydro-1-hydroxynaphthalene-7-yl)-4-pyrimidinamine

KkZz and 3-Y(M-methylamino)carbonylmethyleneoxy|aniline. TYA NMR (0M50-46):6 8.07 (d, 1H, -y (Se) 42) ko 60 b5

3.9 Hz), 7.53-7.45 (ti, 2H), 7.32-7.29 (t, 2), 7.11-7.01 (t, 2H)), 6.49-6, 40 (t, 2H), 6.08-6.00 (t, INU, 4.32 (5, 283, 2.69 and, 2H, 1-8.4 Hz), 7.62 (5, ZNU; LC/MS: purity: 9996; MS (m/i): 420 (MH). 7.3.875 M443-chloro-4-methoxyphenia)-5-fluoro-M2- | Similar to the preparation of IM4-(3,4-styrenedioxyphenyl) -5-fluoro-M2-(3-hydroxyphenyl)-2,4-(3-tihydroxyphenyl)-2,4-pyrimidinediamine pyrimidinediamine, M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-(3 -hydroxyphenyl)-72,4-

K926945) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and 3-hydroxyaniline. IN NMR (С15О0:5 7.91 (0, 1Н, 22 5.4 Hz), 7.71 (0.1Н, 1 2.4 Hz), 7.58 (84, 1Н, 12: 3.0 and 9.0 Hd, 7.15 B 1NI, 7" 8.4 Hz), 7.06 (4, 1H, 1-5 8.7 Hz), 6.92 (Id, 1H, /e 1.5 and 9.9 Hz), 6.88 (IN, )- 1.8 Gy), 6.61 (494, 1H, and 1.2, 2.4, and 8.1 Hz), 3.89 (5, ZN); 19E NMR (282 MHz, SIZO); -46612; LC/MS: purity: 9896; MS (m/z): 362 (MN). 7.3.876 М2,М4-bis(3-chloro-4-methoxyphenia)-5- Similar to the preparation of М2,х4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 70 fluoro-2,4- Pyrimidinedismine (K926946) M2,m4-bis(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinlismine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-methoxyaniline. IN YAM (rM5O-abuv 9.90 (B5, 1H), 9.68 (v5, PN), 8.16 (y, EN, 7- 4.8 Gi), 7.72 (6, EN, 12 2 .4 Hz), 7.650, 1H, 322.1 g), 7.58 (94, 1, 3-24 and 9.0 Hz), 7.38 (09, IN, 2-27 and 9.3 Hz) . (5, ZN); RF/MS: purity: 9995; MS (m/z): 410 (MN). 7.3.877 5-fluoro-M4-4(1,2,3,4-tetrahydro-1- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-14-(3-phenyl-1,2, 4-oxadiazol-5-oxonaphthalen-7-yl)-M2-13-|(M.yl)methyleneoxyphenyl|-2,4-pyrimidineliamine, 5-fluoro-ma-(1,2,3,4-tetrahydro-1 -oxo-methanelaminco)carbonylmethyleneoxy|phenyl| reactions of 2-chloro-5-fluoro-M4-(1,2,3,4-tetraHydro-1-oxo-naphthalene-7-yl4-pyrimylinamine and 3-Y(M-methylamino)carbonylmethyleneoxy |aniline. In YAM" ( pM5O-46);5 9.89 (5, 1NU, 9.55 (B5, IN), 8.17 (4, 1H, 3- 4.2 Gy), 8.04-7.93 (tyu, ZE), 7.32 (y,

HN, 2-2 8.7 Gy), 7.25-7.16 (ta, 213), 7.09 (i, IN, /- 7.5 Hz), 6.52 (64, 1H, 2: 24 and BI Gv), 4.28 (5, 2H), 2.90 (1, 2H, 1-: 6.0 Hn), 2.63 (y, ЗН, 1- 4.8 Hz), 2, 59 (1, 2H, 4- 6.6 Gy), 2.02 (6 A, 7- 6.6 Hn); LC/MS: purity: 9390; MS (m/z): 436 (MN). 7.3.878 5-fluoro-M4-(1,2,3,4-tetrahydro-1- Solution 5-fluoro-M4-(1,2,3,4-tetrahydro-1-oxo-naphthalen-7-yl) - 424134" hydroxyiminonaphthalene-7-5l)-2-13-KM-methylamino)carbonylmethyleneoxy|phenyl|-2,4-pyrimidinediamine (42. mg, 0.095 mmol) and methylamino)carbonylmethyleneoxy|phenyls | of hydroxylamine hydrochloride (8.5 mg, 0.12 mmol) in DMF (1 ml) is heated at 602 -2,4-pyrimidinediamine (K926948) for 12 hours. The reaction mixture is cooled to room temperature and poured into brine (20 ml). With the help of vacuum filtration, a brown solid is isolated, which is then purified by reverse-phase chromatography, retaining 5-fluoro-ma-(1,2,3,4-tetrahydro-1-hydroxyiminonaphthalen-7-yl)-M2-(3- (M. c. si methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine. 1H NMR (0M80-a6ub at 8.13-8.05 (t, 2H), 7.99-7.92 and, 23.7 .77-7.72 (t 1H), 7.33-7.21 (iv, 2H)), 7.14 (4, IN, 15 8.7

GO, 7.10-7.02 (t, 1H), 6.47 (46, IN, 7- 2.4 and 7.5 Hz), 4.30 (in, 2H), 2.90 (B, IN, /- 6.0 Go), 2.70-2.49 (t, 6H), 2.07-1.98 (t, 1H), 1.74 (5, 1H, 4-: 6.6 Hz); LC/MS: purity: 969; MS (mizu; 451 (MN. 7.3.879 5-fluoro-M4-(1,2,3,4-tetrahydro-1-) To the suspension of the solution 5-fluoro-M4-(1,2,3,4-tetrahydro- 1-oxo-naphthalene-7-yl)-M2-|3-10M-hydroxynaphthalene-7-yl)-M2-(3-(0M-methylamino)carbonylmethyleneoxy|pheny)-2,4-npyrimidinediamine (50 mg, 0, Lithium borohydride (5 mg, 0.23 -2,4-pyrimidinediamine (K926949)) is added to 11 mmol) in (se) methylamino)carbonylmethyleneoxy|phenyl| / anhydrous TNE (2.0 ml) at room temperature. The reaction mixture is heated to room temperature, stirred for 8 (e") hours, and then cooled by rapid absorption in methanol. The reaction mixture was poured into water and extracted with ethyl acetate. Purified by preparative TNH. (595 methanol/dichloromethane) to give 5-fluoro-M4-( 1,2,3,4-tetrahydro-1-hydroxynaphthalene 7-yl)-M2-|34(M-methylamino)carbonylmethyleneoxy |phenyl|-2,4-pyrimidinediamine LC/MS: purity: 9695; MS ( m/z): 438 (MH). Ha 7.3.880 M44(3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similar to the preparation of 1M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- (Z-hydroxyphenyl)-2 ,4. (2-(methoxycarbonyl)benzofuran-5-yl|-pyrimidinediamine, M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-(2- with 2.4-pyrimidinediamine (8926950) (methoxycarbonyl)benzofuran-5- il|-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-im4-4(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and 5-amino-2-(methoxycarbonyl)benzofuran. » (0M50-ab):5 9.34 (b, 2H), 8.10-8.07 (t, 2H), 778 (1, 1-2.7 Hz), 7.66-7.53 ( t, 4NU, 7.12 (4, 1Н, 2» 9.3 Gy), 3.87 (5, ЗН)), 3.85 (5, ЗН);

LC/MS: purity: 9995; MS (m/z): 443 (ME). « 7.3.881 Ma-(3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-12,3-dihydro-2-pyrimidinediamine, M4 (3-chloro-4-methoxyphenyl)- 5-fluoro-M2-(2,3-dihydro-2- -o (methoxycarbonyl)benzofuran-5-yl|-2,4-|(methoxycarbonyl)benzofuran-5-yl|-2,4-pyrimidinediamine is obtained as a result reactions of 2-s pyrimidinediamine (K926951) chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and 5-amino-2,3-lihydro-2-(methoxycarbonyl)benzofuran. (0М50-а6):5 10.31 (5, IN), 19.04 (B5, IN), 8.21 p (0 1Н, 154.8 Gy), 7.75 (B 18, 5 3.0 Hz) . , 1- 8.1 Hz), 5.38-5.31 (t, 1H), 3.85 (5, ZI), 3.69 (v, 3), 3.49 (40,

IN and 16.5 Hz); RH/MS; purity: 9996; MS (ml): 446 (MH. 7.3.882 M44(3-chloro-4-trifluoromethoxyphenyl)-3- Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2 ,4-fluoro-M2-|2,3-digylro-2-pyrimidinediamine, MA4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-|2,3-dihydro-2-(methoxycarbonyl)benzofuran- 5-yl|-2,4-|(methoxycarbonyl)benzofuran-5-ylI-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-(o)pyrimidinedigmine (K926953) chloro-M4-(3-chloro-4-trifluoromethoxyphenyl) -5-fluoro-4-pyrimidinamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran. 1H NMR (OM50-46): 5 9.99 (b, 1H), 9.49 (68, ko -y (Se) 42) ko 60 b5

1H)), 8.18 (4, 1H, 72: 4.5 Hz), 8.08 (in, 1H, 32-24 Gy), 7.81-7.78 (pu, IN), 7.49 (8, IN, 2- 8.1 Gy), 7.42 (5, 1), 7.208, EN, 3- 8.1 Hz), 6.78 (4, IN, 32 8.7 Hyd), 5 .36 (t, 1), 3.80-3.47 (t, YAN), 3.20 (44, 1H, 22: 6.0 and 16.5 Gy); LC/MS: purity: 10095; MS (m/z): 500 (Mn. 7.3.883 Ma-3-chloro-4-trifluoromethoxyphenyl)-5- Analogous to the preparation of M4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-M2-I13 -(M-fluoro-m2-12,3-dihydro-2-Y(M-morpholino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, MA (3-chloro-4-2 methylamino)carbonylbenzofuran-5-yl|- | trifluoromethoxyphenyl)-5-fluoro-II-12,3-dihydro-2-II(M-methylamino)carbonyl|benzofuran-5-2,A-pyrimidinediamine (KO26954) and|-2,4-pyrimidinediamine are obtained as a result of reaction 2 -chloro-M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidinamine, methylamine hydrochloride and diisopropylethylamine. 1NMR (rmM5o-a6): 5 9.59 (5, 1H), 9.10 (5, 2H), 8.13-8.10 (t, IN), 8.08-7.98 (t , 1), 7.82 (4, 1H,3- 8.1 Ge), 7.48-7.42 (t, 2H), 7.24 (4, 1H, 7- 8.7 Hz), 6 ,72 (and,

IN, /« 8.7 Hz), 5.05 (44, IN, /- 5.4 and 9.3 Hz), 3.39 (44, IN, 7-2 19.5 and 15.6 Go) , 3.15 (49, 1H, 1- 6.3 x 15.9 Hn), 2.59 (d, ZN, 4- 4.5 Hz); LC/MS: purity: 959; MS (m/z): 499 (MN). 710 7.3.884 Ma-(3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similarly to the preparation of M4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-M2-II3-(M-

H2,3-dihydro-2-I(M-morpholino)carbonylmethyleneoxyphenyl|-7,4-pyrimidinediamine, M4-4(3-xpor-4-methylamino)carbonyl|benzofuran-5-yl)|- | methoxyphenyl)-5-fluoro-M2-(2,3-dihydro-2-Y(M-methylamino)carbonyl|benzofuran-5-1l1-2,4- 2,A-pyrimidinediamine (K926955) pyrimidinediamine is obtained as a result of reaction 2 -chloro-1Ch4-(3-chloro-4-methoxyphenial)-5-fluoro-4-pyrimidinamine, methylamine hydrochloride and diisopropylethylamine. IN YAM (2М50-46):6 9.24 (5, 1Н), 8.99 ( in, 2NU, 8.02 (y, IN, 3- 3.9 Hz, 7.80-7.75 (t, 18), 7.63 (d,

IN, 129.0 Gy), 7.47 (from, 1NU, 7.23 (8, 1H, 1- 8.1 Hu, 7.079, 1H, 34- 8.7 Go), 6.69 (8, IN , 1-8,1

Ty), 5.054, 1H, 1-21 and 9.9 Hz), 3.37 (ai, 1H, 3 10.5 and 15.9 Gu), 3.13 (09, IN, 3- 6.0 and 15.9 Hz), 2.59 (0, ZN, I- 4.5 Hz); LC/MS: purity: 9595; MS (m/z): 445 (MN). 7.3.555 5-fluoro-M2-(2,3-dihydro-2-|(M- Similar to the preparation of M4-(3,5-dichloro-2-hydroxyphenyl)-5-fluoro-M2-| 3-0» methylamino )carbonyl|benzofuran-5-yl|-.|morpholino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, 5 fluoro-IIM2-I2,3-dihydro-2-ma4-isopropoxyphenyl)-2,4-MMM-methylamino)carbonyl |benzofuran-5-yl|-M4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine pyrimidinediamine (K926956) is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(4-isopropoxyphenyl)-4-pyrimidinediamine, methylamine hydrochloride and diisopropylethylamine. "NN NMR (0М50-46):5 9.11 (5, 1Н), 8.92 (v, 1NI), 8.06-7.98 (t, IN), 7.978, 1Н, 324.2 Hz) , 7.60-7.52 (t, ZNU, 7.20 (4, 1H, 7- 8.1

Gy), 6.85 (9, 2H, 1-8.7 and), 6.67 (y, 1H, 7-5 9.0 Hz), 5.04 (49, 1H, le 5.7 and 9 .9 Hz), 4.56 (apithei, IN, 7- 6.6 Hz), 3.36 (44, 1H, 3-: 10.5 and 16.5 Gy), 3.10 (49, IN, I - 5.7 and 15.3 Gy), 2.59 (4, 1H, 1-4.5 Hn), 1.24 (4, EN, 1- 6.6 Hz); LC/MS: purity: 9690; MS (m/z): 438 (MN). 7.3.886 M2,Ma-bis(3-phenylphenyl)-2,4- Similar to the preparation of IM2,IM4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, pyrimidinediamine (2925809) M2М4-bis(3 -phenylphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-aminobiphenyl. LC/MS: purity: 9895; MS (m/z); 415 (MN).

A solution of 2,4-dichloro-5-fluoropyrimidine (0.03 g, 0.18 mmol) and methyl ether and "tyrosine with 7 o dpst tyrosinyl ether) pyrimidine (K940110) (0.14 g, 0.7 mmol) of DMF is heated at a temperature of 100"C for 3 days. The reaction mixture is cooled to room temperature and dissolved in HO (10 ml). Saturate with sodium chloride, then extract with stylacetate (3 x 15 ml), dry over anhydrous sodium sulfate, and the solvent The resulting precipitate is filtered through a silica gel filter (200-400 mesh, hexanes/O de 2/8), obtaining 2-dimethylamine-5-fluoro-M4-(tyrosinyl methyl ether)pyrimidine 940110. 1H NMR (SrIII): b 7.76 apn,a, (Che)

Re 3.2 Gi), 7.00 (H, y, ./- 7.5 Sv), 6.76 (2H, bl 7.5 Hn), 5.20 (a H, y, le 7.5 Hyd), 4.90 (IN, dule 5.0 GI, 3.71 (ZH, 5), 3.14 (2H, ti), 3.08 (6H, 5); purity: 9895; MS (m/zu : 335 (M'H). o 7.3.888 5-fluoro-M2-I3- To a solution of 2-chloro-5-fluoro-M4-(3-aminocarbonylphenyl)-4-pyrimidinamine (0.050g, 0.18 (methylaminocarbonylmethyleneoxy )phenyl| | mmol) to (2 ml) add 3-(methylaminocarbonylmethyleneoxy)aviline (0.1g, 0.5 mmol). h- -M4-(3-aminocarbonylphenyl)-7,4- The mixture is heated in a hermetically closed konbi at 1002 C for 24 pyrimidinylismine (5940299) hours. The reaction mixture is dissolved in HO (10 mL), acidified with 2M NOSI (pH 22), and saturated with sodium chloride. The solid that forms is filtered to give the desired 5-fluoro -M2-I3-(methylaminocarbonylmethyleneoxy)phenyl|-M4-(3-aminocarboniaphenia)-2,4-pyrimidinediamine 940299, Purification can be carried out by the method of filtration through a silica gel filter with 1-595 MeOH in СНоСБ, or by the method of crystallization, using the appropriate a complex of solvents. In another way, as a result of the reaction of an equimolar amount of 2-chloro-5-fluoro-M4-(3-aminocarbonylphenyl)-4- ptyrimidineamine and 3-(methylaminocarbonylmethyleneoxy)aniline in MeOH in a pressurized flask at a temperature of 1102 for 24 hours, or in EUN when heated in a microwave at a temperature of 17572 for 30-60 minutes with subsequent water treatment, the desired substance is also formed. /"H NMR (0M50-46): 5 9.79 (IN, 5), 9.49 (IN, 5), 8.26 (IN, 4-39 Gu, 8.15 (IN, y, 4/2 1 .8 Hz), 8.10-8.02 (ZN, t), 7.68 (IN, 9, 7 7.5 Gy), 7.5 IN, -in 7.9 Go), 7.48 ( IN, 5), 7.38 (2H, t), 7.201, in, ./- 8.4 Hz), 6.60 (IN, 9, 7 9.3 Ty), 4.45 s (2H, 5 ), 2.74 (ZN, y, /: 4.8 Hz); purity: 9595; MS (m/z): 41 (MN). h 7.3.889 5-fluoro-M2-13- Similar to the preparation of 5- fluoro-M2-(3-(methylaminocarbonylmethyleneoxy)phenyl|-M4-(3- i - (methylaminocarbonylmethyleneoxy)phenyl| | aminocarbonylphenyl)-2,4-pyrimidinediamine, 5-fluoro-M2-(3- -M44(3-methyloxycarbonyl -4" (methylaminocarbonylmethyleneoxy)phenyl|-M4-(3-methyloxycarbonyl-4-methoxyphenyl)-2,4- methoxyphenyl)-2,4-pyrimidinediamine pyrimidinediamine is restrained as a result of the reaction of 2-chloro-5-fluoro-M4-(3 -methyloxycarbonyl- 4K940300) 4-methoxyphenyl)-4-pyrimidinamine and 3-(methylaminocarbonylmethyleneoxy aniline)

What 40300. "H NMR (0MI5O-46): δ 9.66 (IN, 5), 9.45 (IN, 5), 8.21 (1Н, 4, /- 3.9 Hz), 8.06 CH, o and), 8.01 (TN, and, 7-27 Gy), 7.35 (2H, t), 7.23 1 Н, 4, /- 9Н), 718 1, и, 8.1 Hn), 6.60 an,a,l- t gy), 4.45 (2H, 5), 3.91 (ZH, 5), 3.84 (ZH, 5), 2.74 (ZH, f, 72 3 .6 Hz); purity: 9399; MS (m/z): 456 (MH). where 7.3.890 5-fluoro-M443-hydroxyphenyl)-M2-(3- Analogously to the preparation of 5-fluoro-M2-I3-( methylaminocarbonylmethyleneoxy)phenyl|-M4-(3- - methyloxycarbonyl-4-methoxyphenyl)-2,4- | aminocarbonylphenyl)-2.4-pyrimidinediamine, 5-fluoro-MA-(3-hydroxyphenyl)- M2-(3- (Ce) 42) ko 60 b5 pyrimidinediamine (K940301) methyloxycarbonyl-4-methoxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(3-hydroxyphenyl)-4-pyrimylamine and 3-methyloxycarbonyl l- 4-Methoxyaniline B940301. "H NMR (OM5O-6); 5 9.93 (IN, 5), 9.79 (TN, 5), 9.54 (TN, 8), 8.26

IN, c, le 4.5 GG), 7.92 (1 H, 5), 7.81 (1, 4, le 9.3 Hm, le 2.7 C), 7.32 (1 H, b, le 8 Go), 7.29-7.13 (ZN, t), 6.64 (IN, 4, /2 8.1 Gy), 3.89 (ZN, 8), 3.84 (ZN, 5) ; purity: 9790; MS (m/z): 385 (MN). 7.3.891 5-fluoro-M4-(3-methylaminocarbonyl-4- Mixture of 2-chloro-5-fluoro-M4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidinamine (0.15 g, methoxyphenyl)-M2 -methyl-2,4- 0.4 mmol), methylamine hydrochloride (0.324 g, 48 mmol) and diisopropylethylamine (0.84 pyrimidinediamine (5940304) mL, 48 mmol) in MeOH (2 mL) are heated in a sealed flask at 1002 C for 24 hours (after which TINTH is carried out). The reaction mixture was cooled to room temperature and dissolved in H.O. (20 ml). The solid substance is filtered, washed with water and dried, obtaining 5-fluoro-M4-(3-methylaminocarbonyl-4-methoxyphenyl)-M2-methyl-2.4-pyrimidinediamine 940304. "H NMR (2M50-86): 5 10.65 (IN , 5), 848 (IN, 5), 8.29 (7Н, t), 7.93 (1Н. t), 7.28 (1Н, 4, 7-9 Hz), 4.00 (ЗН, 5 ), 2.94 (ZH, 5), 2.90 (ZH, y, le 4.5 Hz); purity; 9096; MS (m/z): 306 (MH). 7.3.,892 5-fluoro-M2- |3- Similar to the preparation of 5-fluoro-M2-|3-(methylaminocarbonylmethyleneoxy)phenyl|-M4-4(3- (methylaminocarbonylmethyleneoxy)phenyl) | aminocarbonylphenyl)-2,4-pyrimidinediamine, 5-fluoro-M2-13- - M4-(3-methylaminocarbonyl.4-(methylaminocarbonylmethyleneoxy)phenyl|-M4-(3-methylaminocarbonyl-4-methoxyphenyl)-2,4- methoxyphenyl)-2,4-trymidinediamine pyrimidinediamine K940306 is obtained as a result of the reaction of 2-chloro-5 -fluoro-M4-443- (K940306) methylaminocarbonyl-4-methoxyphenyl)-4-pyrimidinamine and 3-(methylaminocarbonylmethyleneoxy)aniline. "H NMR (DM5O0-46): 5 9.28 (1H, 5), 9.21 (1H, 5), 8.12 (1H, 4, /- 3.9 Hn), 8.06 (1H, 8, /e: 2.7 Gy), 7.99 (IN, t), 7, 89 (I N, da, le 9.3 Hu, /- 2.7

Gy), 7.52 (IN, a, 7 4.9 Gy), 7.1 (IN, 67 2.1 Hz, 7.37 (1H, 4, 7.5 Hz), 70 (IN, /- 8.1 Gy), 6.83 (1 H, a, /- 9 Gy), 6.53 (1H, ab, le B God, le 18 that 4.40 (2H, 5), 3.82 (ZH , 5), 2.96 (ZN. d, ich 5.1 Gy), 2.73 (ZA, d, lk 4.5 Gy); purity: 9395; MS (m/z): 4535 (MN). 7.3. 893 (VU M2-13- Analogously to the preparation of 5-fluoro-M4-(3-methylaminocarbonyl-4-methoxyphenyl)-M2-methyl-(dihydroxypropylaminocarbonylmethylene | 2,4-pyrimidinediamine, (K)-M2-(3-0М-2 ,3-oxy)-phenyl|-5-fluoro-M4-(3-dihydroxyprotylamino)carbonylmethyleneoxyphenyl)-3-fluoro-M4-(3-isopropylphenyl)-2,4- isopropylphenyl)-2,4-pyrimidinediamine pyrimidinediamine is obtained in as a result of the reaction of 5-fluoro-M4-(3-isopropylphenyl)-M2-(1- (8940307) methoxycarbonylmethylhexyphenyl)-2,4-pyrimidinedimine and (B.)-3-amino-1,2-propanediol 1940307. "Н ЯМ (OM5O-46): 5 9.96 (1H, 5), 9.50 (1H, 8), 8.29 41, 4, /7- 4.5 Hz), 7.98 (1H, en 5.5 Gi), 7.77 (IN, 0.72 i), 7.57 (H, 5), 7.37 (He, le 7.8 C), 7.30-7.22 (ZA, t), 72, a, le 7.8 Gy), 6.79 (1H, 9, Le 7.5 Hz), 4.47 (2H, 5 ), 3.62 (1H, then), 3.38 (ZA, t), 3.15

OH, t), 94 (1H, acipi,./- 6.9 Ha), 1.27 (6H, 6, 6.9 Hz); purity: 9995; MS (m/z): 469 (M), 470 (Mn. shi -86-- w TT with 7.3.894 MA43-tert-butylphenyl)-5-fluoro-M2-13- 1 Analogously to the preparation of 5-fluoro-M4 -(3-methylaminocarbonyl-4-methoxyphenyl)-M2-methyl-He) (1,1-dimethyl-2-2,4-pyrimidinediamine, M4-(3-tert-butylphenyl)-5-fluoro-M2-13 -(11,1-dimethyl-2- hydroxyethylaminocarbonylmethylevokei)- | hydroxyethylaminocarbonylmethyleneoxy)-phenyl|.2,4-pyrimidinediamine is obtained in phenyl)-2,4-pyrimidinediamine (940308) as a result of the reaction M4-(3-tert-butylphenyl)- 5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine and 2-amino-2-methyl-1-propanol

K940308. "H NMR (0M50-45): 6 9.38 (IN, 5), 9.28 (1H, 5), 8.20 (18, y, /- 3.9 iv), 7.99 (TIN, 4, le 7.5 g), 7601,» 21 Sv), 7.46 (1H, 5), 7.37 (2H, ie 7.9 Go), 730 (IN, 5), 7.19 (Che )

OH, 5-79 Hz), 6.56 (EN, ay, ee 7.5 Hz, le 1.5 Hz), 5.06 (IN, M, 7 5.7 Hz), 4.37 (ZN, 5), 3.40 (2Н, t), 1.36 (9Н, 5), 1.32 (ЕН, 5); purity: 9395; MS (m/z); 482 (MN). Ge 7.3.895 Ma-(3-aminomethylenephenyl)-5-fluoro-M2- Mixture of Ma-I341M-tert-butoxycarbonyl-M-aminomethylene)-phenyl|-2-chloro-5-fluoro-4- (3. pyrimidineamine and 3-(methylaminocarbonylmethyleneoxy)aniline in MeOH is heated in a (methylaminocarbonylmethyleneoxy)phenyl|/ hermetically sealed flask at 1002C for 12 hours. , The resulting precipitate is filtered through a silica gel filter (mesh size 200-400, EtOAc/MeOH sem (OM MH,)95: 5), obtaining the desired substance M44(3-aminomethylenephenyl)-5-fluoro-M2-Y13-(methylaminocarboxylmethyleneoxy)phenyl |-2,4-pyrimidinediamine K940309. "H NMR (OM5O0-c 466941 (NN, 5), 9.23 (1, 5), 8.20 (1, y, le 3.9 Si), 8.00 (IN, t), 7.78 (IN, 8), 7.72 (1H, y, 72 gy), 7.46 (1H, 5), 7.42-7.33 (2H, t), 7 ,21 (IN, blk 7.8 Hn), 7.14 (IN, a, le 7.8 Go), 6.59 (1, ad, le 8.1 Hz, 7-24 HY), 4, 42 (2H, 5), 3.79 (2H, 5), 2.74 (ZH, 4, /7- 4.8 Go); purity: 9855; MS (m/z): 397 ( MN). 7.3.896 m4-13-(2-(M4-(3-aminomethylenephenyl)-5- | Mixture M4-|3-(M-methylaminomethylene)-phenyl-2-chloro-5-fluoro-4-pyrimidinamine (0, 05 g, 0.18 " fluoro-4-pyrimidinamine)-M-mmol) and 3-(methylaminocarbonylmethyleneoxy aniline (0.04 g, 0.22 mmol) in EYN (0.5 ml) methylaminomethylene)-phenyl|-5 -fluorine-M2- | subjected to microwave heating at 175 "C for 35 minutes. After water

I3- treatments restrain the desired substance М4-(3-(2-(М4-(3-aminomethylenephenyl)-5-fluoro-4- shsh (methylaminocarbonylmethyleneoxy)phenyl | pyrimidineamine)-M-methylaminomethylene)-phenyl|-5-fluoro- M2-13-c-2,4-pyrimidinamine (KU40311) (methylaminocarbonylmethyleneoxy)phenyl|-2,4-pyrimidinamine K940311. "H NMR (OM50- abu: 5 9.48 (IN, 5), 9.31 (1 . , 5), 7.49 (OH, pt), 7.41 (IN, /- 8.1 Hz), 7.36 (2H, t), 7.22 (1H, and 7- 8.4 Ha) . .54 (1H, yes, le 7.8

Hz,./- 2.4 Hn), 4.93 (2H, 5), 4.46 (2H, 5), 4.45 (2H, 5), 3.28 (ЗН, и, /« ЗН) , 2.73 (6H, tu; purity: 9895; MS (m/z): 684 (M), 685 (MH). 7.3.897 5-fluoro-M2-(3- Analogous to the preparation of 5-fluoro-M2- 13-(methylaminocarbonylmethyleneoxy)phenyl|-M4-(3- (ee) (methylaminocarbonylmethyleneoxy)phenyl| ) aminocarbonylphenyl)-2,4-pyrimidinediamine, 5-fluoro-M2-(3- -M443-iso-propylaminocarbonyl-4- ( methylaminocarbonylmethyleneoxy)phenyl|-M4-(3-iso-propylaminocarbonyl-4-methoxyphenyl)-methoxyphenyl)-2,4-pyrimidinediamine 2,4-pyrimidinedigmine 4940312 is obtained as a result of the reaction of 2-chloro-5-fluoro-Mm4-(3- M-iz0-io) (8940312) propylaminomethiden-4-methoxyphenyl)-4-pyrimidinamine and 3- -y (Ce) 42) ko 60 b5

(89403123 (methylaminocarbonylmethyleneoxy)aniline. "NYAM (0М50-а6); 5 10.09 (IN, 5), 9.88 I, 5), 8.25 (1Н, и, / 4.8 Hz), 8, 07 (IN, y, len 2.7 Go), 8.05 (IN, p), 7.81 (IN, ad, le 9 Hz, le 2.7

Ha), 7.63 (1H, 5), 7.25 (2H, t), 717.1, 6 7-2 8.25 Hz), 6.91 (IN, y, 7-9 Hz), 6.68 (1H, y, 4 8.1 p), 4.42 (2H, 5), 3.85 (1H, t), 3.81 (ЗН, 5), 2.72 (ЗН, а, /- 4 ,2 Gy), 1.30 (6H, y, /2 6 Hz); purity: 9795; MS (m/z): 483 (MN). 7.3.898 5-fluoro-M2-13- Analogously to the preparation of 5-fluoro-M2-I3-(methylaminocarbonylmethyleneoxy)phenyl|-M4-(3-(methylaminocarbonylmethyleneoxy)phenyl|aminocarbonylphenyl)-2,4-pyrimidinediamine, 5-fluoro- h2-I3- -M4-(3-(M-morpholinomethylene)-4- (methylaminocarbonylmethyleneoxy)phenyl|-M4-I3-(/M-morpholinomethylene)-4-methoxyphenyl|- methoxyphenyl)|-2,4-pyrimidinediamine 2 ... -4b): 6 9.33 (1H, 5), 9.21 (1, 5), 8.15 (IN, 4, /- 3.6 Hz), 8.04 (1H, 4, le 4, 8 Gi), 7.82 (1H, 49, Le 9 Hn, 2-27 Gu, 7.57 IN, a, - 3), 747 N.B le 1.95 Hz), 7.34 (IN, t ), 718 AN, 6 ie 8.1 Sv), 7.04 (TN, 4, 7-9 Hz, 6.56 (IN, 44.7: 8.4 Hz, 2.1 Hz). 4.40 (2Н , 5). .5 Hz), 2.46 (4H, t); purity: 9795; MS (m/z): 497 (MH). 7.3.899 M2-(3-chloro-4-hydroxy-5-methylphenyl)-5 Similarly, p regurgitation of 5-fluoro-M2-/3-(methylaminocarbonylmethyleneoxy)phenyl|- M44(3. fluoro-M4-(3-(M-morpholinomethylene)-4-aminocarbonylphenyl)-2,4-pyrimidinediamine, 1/2-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoromethoxyphenyl)-2 ,4-pyrimidinediamine M4-I34(M-morpholinomethylene)-4-methoxyphenyl|-2,4-pyrimidinediamine 940316 is obtained in (8940316) as a result of the reaction of M2-chloro-5-fluoro-M4-I3-(M-morpholinomethylene)-4 -methoxyphenyl|-4-pyrimidinamine and 4-amino-2-chloro-b-methylphenol, "H NMR (0M5O-46): 5 9528 (1H, 5), 9.01 (IN, 8), 8.651, 5) , 8.1! (IN, y, le 3.9 Hz), 7.76 (19, da, le 9 Hn, le Z Gi), 7.61 (1H, I,

I-24 Hn), 7.50 (1H, 4» 2.7 Go), 7.30 (1, 4, 2 2, Go), 704 1 H, 8, /7- 8.7 Gy), 3.87 (ZM, 5), 3.63 (AN. 1, /- 4.3 Hz), 3.52 (2H, 5), 2.45 (AN, t), 2.17 (ZN, in ); purity: 9795; MS (m/z): 474 (MH. 7.3.900 M4-(3-M-methylaminomethylenephenyl)-5- Analogous to the preparation of 5-fluoro-M2-13-(methylaminocarbonylmethyleneoxy)phenyl|-M4-(3-fluoro-M2 -|3-aminocarbonylphenyl)-2,4-pyrimidinediamic, M4-(3-M-methylaminomethylenephenyl)-5-fluoro-(methylaminocarbonylmethyleneoxy)phenyl| | M2-(3-(methylaminocaronylmethyleneoxy)phenia)-2,4-pyrimidinediamine K940317 are obtained in -2,4-pyrimidinediamine (K940317) as a result of the reaction of M4-|34(M-tert-butoxycarbonyl-M-methylaminomethylene)-phenyl|-2-chloro-5-fgor-4-pyrimidinamine and 3-(methylaminocarbonylmethyleneoxy aniline). "H NMR (OM50- ab Vo (IN, 85), 9.31 (IN, 5), 9.29 (1H, 5), 8.20 (IN, d, /- Z Hz), 8.05 IN . (IN, a, 7.5 Hz), 6.59 (IN, a, /- 9.6 Hn), 4.43 (2H, 5), 3.7! (2H, 5), 2.75 ( ZN, F,./- 4.2 Hz), 2.35 (ZN, 5); purity: 83.995; MS (m/z): 411 (MN. 7.3.901 M2-(3-chloro-4-tihydroxy -5-methylphenyl)-5- | Similar to the preparation of 5-fluoro-M2-|3-(methylaminocarbonylmethyleneoxyphenyl!-M4-(3- fluoro -Mma-I13-(M-piperazinomethylene)-4-aminocarbonylphenyl)-2,4-pyrimidinediamine, M2-(3-chloro-4-tihydroxy-5-methylphenyl)-5-fluoro-si methoxyphenyl-2,4-pyrimidinediamine Ma4-I34(Mpiperazinomethylene)-4-methoxyphenyl-2,4-pyrimidinediamine NU40318 is obtained in (K940318) as a result of the reaction of Ma-(3-0h-piperazinomethylene)-4-methoxyphenyl|-2-chloro-5-fluoro-4-He ) of pyrimidine and 4-amino-2-chloro-b-methylphenol. /"H NMR (OM50-46): 6 9.27 (IN, 5), 9.00 (1H, 5), 8.10 (1H, 4, 7- 3.6 Hz). 7.75 (1H , yes, /- 8.7 Hz, I- 2.7 Hz), 7.61 (1H, y, 7" 24

Gsh), 7.491, a, ie 24 Hz), 731 (IN, a, le 24 gy), 7.03 (1H, y. ./- 9 Ha), 3.86 (ZN, 5), 3.49 (IN , 8), 2.75 (AN, 5, i- 4.65 Hn), 2.39 (AN, t), 2.17 (ZN, 5); purity: 9595; MS (m/z): 473 (MH. 7-3.902 Ma-(34(M-tert-butoxycarbonyl-M-iz0-) Analogously to the preparation of 5-fluoro-M2-|3-(methylaminocarbonylmethyleneoxy)phenylI-M4-(3- with propylaminomethylene)-4-methoxyphenyl)-aminocarbonylphenyl)-2,4-pyrimidinediamine, MA-(3-(M-pregy-butoxycarbonyl-M-/i30-5-fluoro-M2-(3-propylaminomethylene)-4-methoxyphenyl )-5-fluoro-M2-(3- (e") (methylaminocarbonylmethyleneoxy)phenyl | (methylaminocarbonylmethyleneoxy)phenyl-2,4-pyrimidinediamine E940319 is obtained in -2,A-pyrimidinediamine (8940319) as a result of the reaction M4-(34( M-pret-butoxycarbonyl-M-iso-propylaminomethylene)-4-methoxyphenyl)-2-chloro-5-fluoro-4-pyrimidinamine and 3-h-(methylaminocarbonylmethyleneoxyaniline), "H NMR (OM5O-46): 6 9, 44 (1H, 5), 8.95 (1H, 5), 8.15 IN, y, le: 3.6 Gu, 8.06 (1H, t), 7.83 (1H, ti, 7.74 (IN, t), 7.56 (IN, lu), 7.37 (IN, tu, sem 720 PN, g, le 7.9 Hn), 7.02 (1H, d, le 9.3 Go, 6.57 (AN, 4, le 7.8 Hyd), 4.44 (OH, 5), 4.42 (IN, p), 4.33 (2H, 5), 3.89 (ZN, 8) . at

Hz); purity: 9895; MS (m/z): 569 (MN). 7.3.903 M443-M,M-dimethylaminomethylene-4- Similar to the preparation of 5-fluoro-Mm2-|3-(methylaminocarboni lmethyleneoxy)phenyl)- M4-(3- methoxyphenyl)-5-fluoro-M2-13-aminocarbonylphenyl)- 2,4-pyrimidinediamine, M4-3-M,M-dimethylaminomethylene-4- (methylaminocarbonylmethyleneoxyphenyl) | | methoxyphenyl)-5-fluoro-M2-(3-(methylaminocarbonylmethyleneoxy)phenyl|-2,4-pyrimidinediamine -2,4-pyrimidinediamine (К940321) К940321 is obtained as a result of the reaction of 2-chloro-ХМ4-(3-М.М- dimethylaminomethylene-4-methoxyphenin)-5-fluoro-4-pyrimidinamine and 3-(methylaminocarbonylmethyleneoxy aniline. " "H NMR (0M50-6y: 5 9.32 (1, 5), 9.23 (IN, 5), 8 ,14 (IN, y, le 3.9 Gy), 8.05 (IN, t), 7.83 an,aa,y- 8.7 Gu, /- 2.4 Hz), 7.55 (1Н , y, Le 2.4 Gy), 7.45 (IN, 5), 7.36 (IN, y, le 8.4 Hz), shsh 7181, le 81 Hyd, 7.03 (1H, 4, 7 : 9 Hn), 6.56 (1H, ay, le 7.2 Hz, le 1.5 Hz), BA (2H, 5y, s 3.86(3H, 5), 2.73 (ZH, 9, ./- 4.5 Gy), 2.24 (OH, 5); purity: 91.89; MS (mi); 455 (MH). h 7.3.904 Mma-((2,2-dimethyl-4H- benzori Yaoxazin- | Analogous to the preparation of 5-fluoro-M2-(3-(methylaminocarbonylmethyleneoxy)phenyl|-M4-(3- and 3-mono)-6-yl|-5-fluoro-Yi2-Yi3-aminocarbonylphenyl)-2 ,4-pyrimidinediaminchu, M4-I(2,2-dimethyl-4H-benzo| I oxazine-3-(methylaminocarbonylmethyleneoxy)phenyl| | -2,4-pyrimidinediamine -2,4-pyrimidinediamine (K940323) K940323 is obtained as a result of the reaction of 2-chloro-M4A-K2,2-dimethyl-4H-benzo| 1, Choxazin-3-mono)-6-yl|-5-fluoro-2-pyrimidinamine and 3-(methylaminocarbonylmethyleneoxy aniline.

NMR (PM8O-46): 6 19.70 (1H, 5), 9.45 (IN, 5), 9.19 (1H, 8), 8.17 (1H, 4, ./- 3.9 Gy ), 8.05 (IN, (o e | t), 7.43-7.34 (AN, t), 7.17 (1H, 6, .7-8.25 Gy), 6.98 (EN , b, ie 8.4 Go), 6.56 (1H, ay, /e 7.8

Hz, 2.1 5), 4.25 (NN, 5), 2.74 (ZH, a, /- 4.5 Gy), 1.5 (6H, zu; purity: 98.75; MS (m /3): ko -y (Se) 42) ko 60 b5

74.54 Ma-(2,2-pimethyl-3-oxo-4H- Analogously to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-benz 1,4 Zoxazin-6-yl)-5 -fluoro-M2-(3-13-(M-methylamino)jarbonylmethyleneoxyphenyl)|-2,4-pyrkmidinediamine, M4-(2,2-dimethyl-3-methoxy-5-trifluoromethylphenyl)-2,4-oxo-4H -benz(1,4|oxazin-6-yl)-5-fluoro-M2-(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine (8927065) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-( 2,2-dimethyl-3-oxo-4H-benz|1,4oxazin-6-yl)-5-fluoro-4-pyrimidinamine and 33-methoxy-3-trifluoromethylaniline. /N

NMR (0M50-46): δ 10.57 (8, IN), 9.41 (8, IN), 9.38 (5, 1H), 8.11 (4, IN, 72 3.6 Gy), 7.65 (5,

IN, 7.59 (5, 1H), 7.30 (ta, 1H), 7.18 (5, 180), 6.85 (4, 1H, 75 8.7 Hz), 6.69 (5, 1H) , 3.70 (6, ЗН), 1.39 (5, 6Н); LC/MS: purity: 989; MS (m/z): 478 (MN). 74.55 142-(2,6-dimethoxypyrid-3-4l)-M4-(2,2- Analogously to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2- dimethyl-3-oxo-4H- benz|1,4|oxazine-b-Y3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimylinltamine, M2-(2,6-yn)-5-fluoro-2,4-pyrimidinediamine dimethoxypyryl-3-yl )-M4-42,2-dimethyl-Z"oxo-4H-benz 1, Noxazin-b-yl)-5-fluoro-2.4- (K927068) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2 -dimethyl-3-oxo-4H-benzyl,poxazine-b-yl)-5-fluoro-4-pyrimidinamine and 3-amino-?,b-dimethoxypyridine. /Н 170 NMR (0М50-а6): 5 10.56 (5, 1Н)), 9.28 (в, 10), 7.87 (т, 2Н)), 7.67 (5, 13), 7 ... 4 YEARS, 3.87 (5, ZNU, 3.82 5,

ЗН), 1.39 (5, 6Н); LC/MS: purity: 9795; MS (m/z): 441 (MN). 7.4.56 Х2-(2,6-dimethylphenyl)-М4-(2,2-dimethyl- | Similar to the preparation of М4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-М2- 3-oxo-4H-benz | 1,4 oxazine-6-1l)-5-(3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimicindiamine, M2-(2,6-fluoro-2,4-pyrimidinedimmium (5927069) dimethylphenyl)-M4 -(2,2-dimethyl-3-oxo-4H-benz| 1,4 oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2- dimethyl-3-oxo-4H-benz1,oxazin-o-yl)-5-fluoro-4-pyrimidinamine 3,5-dimethylaniline NMR (rmM50-abu: 610.74 (5, IN), 10.40 (L5 , NO), 10.10 (65, 15, 8.25 (64, 1H), 7.24 940, 1H, 1-5 2.4 and 8.1 Gy), 7.14(5, 1, 7 .09 (68, 2), 6.92 (8, 1H, 2- 9.0 Hz), 6.68 (65, 1NU, 2.16 (5, 6NI), 1.40 (5, 6);

VK/MS: purity: 9596; MS (m/z): 408 (MN). 74.57 M4-(2-aminopyrid-6-yl)-1h2-(2,6- Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-dimethylphenyl)-5-fluoro-2,4 - I3-(m-methylamino)carbonylmethyleneoxyphenyl|-2,2-pyrimidinediamine, M4-(2-minopyrid-b-pyrimidinediamine (KU27078) ip)-m2-(2,6-dimethylphenyl)-5-fluoro-2,4 -pyrimidinediamine is obtained as a result of the reaction of M4-(2-amicopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidinamine and 3,5-dimethylaniline, 'H NMR (0M50-a6); 5 8.33 (p5, 1H), 7.78 (I, IN, 7: 8.7 Gy), 7.29 (B5, 2NI), 6.77 (5, 1H, I- 5.4 Go), 6 .61 (B5, 1), 6.47 (0, 1H, 1: 8.7 Hz), 2.22 (5, 6NU; PH/MS: purity: 10095; MS (m/z): 325 (MH 7.4.58 M44(3,4-dichlorophenyl)-M2-(2,6- Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-dimethylphenyl)-5-fluoro-2,4 - (3-(m-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-pyrimidinediamine (K927079) dichlorophenyl)-M2-(2,6-dimethiaphenia)-5-fluoro-2,4- pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidinamine and 3,5-limethylaniline.

NMR (РМ5О-46): 5 9.57 (8, IN), 9.18 (5, 1), 8.16 (4, 1Н, 1- 3.6 Г 3, 8.04 (4, 1Н, 1- 27 g), 7.81 (46, 1H,3-2.7 and 9.3 Hz), 7.52 (4, 1H, 72 9.0 Hu, 7.22 (in, 2H), 6.54 (I, IN, IN 2 Go, or 2.17 (5, 6H)U; EX/MS: purity: 9295; MS (m/z): 377 (M). 7.A.59 M2-(2, 6-dimethylphenyl)- M4-(3,4- Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2- sem ethylenedioxyphenyl)-5-fluoro-2,4- 3-(M-methylamino )carbonylmethyleneoxyphenyl!-2,4-pyrimidinediamine, M247,6-pyrimidinediamine (KU27086) dimethylphenyl)-4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained in c " as a result of the reaction of 2-chloro- Mm4-(3,4-ethalenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3,5-dimethylaniline. 1H NMR (0M50-463: 59.11 (5, 18), 9.01 (5.1) , 8.02 a, H, 7: 3.9 Hz 7.26 (t, ZNU, 7.18 (t, IN), 6.78 (6, 1H, 1: 8.7 Hz), 6.49 (65 , 1H), 4.21 (5, 4H), 2.16 (5, 6H);

LC/MS: purity: 9796; MS (m/z): 367 (MN). 74.60 M2-(2,6-dimethylphenyl)-5-fluoro-M4- Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2- (indol-b-yl)-2,4- pyrimidinediamine 13-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(2,6- (8927088) dimethylphenyl)-5-fluoro-M4-(indop-6-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(indol-b-yl)-4-pyrimidinamine and 3,5-dimethylaniline. "H NMR (SOCIz): shsh 88.12 (5, IN), 7.95 (5, IN), 7.92 (0, 1.72 3.3 Hn), 7.60 (8, 1Н, 1 -2 8.7 Hz), 7.19 6, IN, 1 s 2.7), 7.15(5.2Н), 7.07 (90, 1Н, 7- 1.5 and 8.1 Hz), 6 .93 (5, 18), 6.86 (65, 1H), 6.65 (5, IN), and 6.54 (t, 1H), 2.19 (5, 6H); LC/MS: purity : 10095; MS (m/z): 348 (MN. p » 7.4-61 M442-(0M-acetylamino)pyrid-b-yl)|-M2- Similar to the preparation of MA-"(3Z-chloro-4-methoxycarbonylmethyleneoxyphenyl) - 5-fluoro-M2-(3,5-dimethylphenyl)-5-fluoro-2,4-13-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(24(0M-trimidinediamine) (K927092) acetylamino)pyrid-b-yl-M2-(3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinedismine is obtained as a result of the reaction M4-12-(M-acetylamino)pyrid-b-yl|-2-chloro -5-fluoro-2,4-pyrimidinamine and 3,5-dimistylaniline, /"H NMR (PM5O-46); δ 10.23 (5, IN), 9.18 (5, 1), 8.99 ( 65, IN), 8.17 o (t, 1H), 7.73 (t, 2H), 7.28 (5, IN), 7.25 (5, 2H)), 6.55 (t, 11 ), 2.20 (5, ZNU, 2.17 (in, ZNU;

LC/MS: purity: 8095; MS (m/z): 367 (MN). ko 7.462 2-(3,5-dimethylphenyl)-5-fluoro-M4-124(M- | Similar to the preparation of IM4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-methylamino)carbonylaminopyrid-b-yl - (3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(3,5- or 2,4-pyrimidinediamine (K927098) dimethylphenyl)-5-fluoro-M4-|2-(M-methylamino )carbonylaminopyrid-b-1l|-2,4-pyrimidinediamine is restrained as a result of the reaction of 2-chloro-5-fluoro-1Ch4-(2-(X-methylamino)carbonylaminopyrid-b-yl|-2,4-pyrimidinediamine and 3, 5-dimethylaniline. "H NMR. (se) (rm5o-ab): δ 9.73 (5, 1H), 9.26 (5. 10), 9.21 (5, 1), 8.77 (65 , 1, 8.214, 1H,1- 3.3 Gy), 7.794, 1H, 27.5 Hz), 7.57 1H, 3 7.8 Hz), 7.27 (5, 2H), 6.62 ( 8, IN, 1-- 8.4 G i), 6.55 (5,

GI IN), 2.744, ZN, In 42 Hz), 2.20 (5, 6Н); LC/MS: purity: 10090; MS (m/z): 382 (MN). 7.4.63 M2-(3,5-dimethylphenyl)-5-fluoro-M4-11-(M- | Similar to the preparation of 2-chloro-5-fluoro-M4-|2-(M-methylamino)carbonylaminopyrid»b-yl - methylamino)carbonylindole-b-1l1-2,4-2,4-pyrimylamine, M2-(3,5-dimethylphenyl)-5-fluoro-M4-(1-(M-methylaminocarbonyl)indole-b-pyrimidinediamine ( 927099 yl)-2,4-thyrimidinediamine is obtained as a result of the reaction M2-(3,5-dimethylphenyl)-5-fluoro-M4-ko 60 b5

CHY pyrimidinediamine (K927099) (indole-b-ia)-2.A-pyrimidinediamine and triphosgene. RH/MS; purity; 5255; MS (mesh): 405 (Mn. 74.64 Ma-(2-aminopyrid-b-yl)-M2-(3-chloro-4- Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2 - trifluoromethoxyphenyl)-5-fluoro-2,4- I3-(M-methylamino)carbonyl styreneoxyphenyl|-2,4-pyrimidinediamine, M4-(2-aminopyrid-b-pyrimidinediamine (9270813 yl)-Mm2-(3-chloro- 4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(2-aminopyrid-b-yl)-2-chloro-5-fluoro-4-pyrimidinamine and 3-chloro-4-trifluoromethoxyaniline. "H NMR (0M50-46): 5 9.66 (z, IN), 8.94 (5, 18), 8.16 (4, 1H, 72 3.0

Gy), 8.12 (Bai, 18), 7.65 (69, 1H, 7- 9.0 Gy), 7.39 (t, 2H), 7.22 (t, TO), 6.204, 1H, 15 7 ,8

Hn), 5.84 (vv, 2H); LC/MS: purity: 9595; MS (m/z): 415 (MN). 7.4.65 M2-(3-chloro-4-trifluoromethoxyphenyl)-M4- | Similarly to the preparation of Mm4-(3-chloro-4-methoxycarbonylmethyleneoxyphentyl)-5-fluoro-M2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4- 13-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4- pyrimidinediamine, M2-(3-chloro-4-pyrimidinediamine (K927085) trifluoromethoxyphenyl)-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine 70 are obtained as a result of the reaction of 2-chloro-Ma-( 3,4-styrenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3-chloro-4-trifluoromethoxyaniline. IN NMR (PM50-4y6): and 9.56 (5, 1H), 9.28 (5.1H0, 8119 (y, 1H,3- 3.9 Gy), 8.05 (y, 1H, 2- 24 Hz), 7.60 (ad, IN, 3 2.7 and 9.0 Hz), 7.34 (db, 18.15 1.2 and 9.0 Hz), 724.1, 24 Hz), 7.12 (44, 18, 1-24 and 8.7 Gy), 6.81 (8, 1H, 7 8.4 Hz), 22 (5, 4H); LC/MS: purity: 9095; MS (m/z): 457 (MN). 7.A.66 M44(2-aminopyrid-6-yl)-M2-(3-chloro-4- Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2- methoxyphenyl)-5- fluoro-2,4-3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(2-aminopyrid-b-pyrimidinediamine (2927082) yl)uM2-(3-chloro-4-methoxyphenyl)-5 -fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of Mach2""aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidinamine and 3-chloro-4"methoxyaniline. "H NMR (YBM5O-y6) : 5 9.23 (5, IN), 8.68 (5, 1H)), 8.09 (d, IN, 2-3.3 Gy), 7.86 (IN, 1-3, g), 7.46 (Ly, 1, 1-96 Hz), 7.34 (t, ZA), 7.02 (y, 1H, 15 90 Gy), 6.17 94, 1H, 127.2 Gy), 5 .80 (t, 2H), 3.78 (5, 3); LC/MS: purity: 10005; MS (m/z); 361. 2,4-Y3-(M-methylamino)carbonylmethyleneoxyphenyl)|-2,4-pyrimidinediamine, M2-(3-chloro-4-pyrimidinediamine (K927084) methoxyphenyl)-M4-(3,4-ethylenelioxyphenyl)-5-fluoro -2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-chloro-4-methoxyaniline. "I NMR (0M50-46): 5 9.15 (5, 1H), 9.12 (5, 1), 8.02 (4, 18, 7-39 g), 7.89 (4.1 H,2- 2.4 g), 7.48 (40, 1H, 1-2.4 and 6.3 P), 7.26 (4, 1H, 2-7.4 Go), 7.16 (49, 1H, 1-2.7 and 93 Gy), 7.00 (f1H, 12 8.7 Hn), 6.79 (4, 1H, 1- 8.7 Hz), 4.22 (5, 4H), 3 .78 (5, ZN);

LC/MS: purity: 9692; MS (m/z)y: 403 (MN). 7.4.58 M2-(3-chloro-4-methoxyphenyl)-5-fluoro-1M4- | Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenia)-5-fluoro- M2-(indol-b-yl)-2,4-pyrimidinediamine and 3-(m-methylamino)carbonylmethyleneoxyphenyl)|-2,4-pyrimidinediamine, M2-(3-chloro-4-se (5927091) i methoxyphenyl)-5-fluoro-MA indole-b-1p)-2,4-pyrimidinediamine is obtained as a result of the reaction

AND

(K927091) 2-chloro-5-fluoro-M4-(indol-6-yl)-4-pyrimidinamine and 3-chloro-4-methoxyaniline. H 'YAME o) (SOS): ГИ 8.25 (p5, 1NI), 8.03 (b5, IN), 7.89 (4, 1Н, 1- 3.3 Ги), 7.82 (4, IN, 2-2.7 Gy), 7.59 (8.18, 1-8.4 HZ), 7.20 (t, 1), 7.15 (4, IN, 3 2.4 Hp), 7.07 (vv, 1H), 6.96 (4d, IN, 12 2.1 and 8.4 Gy), 6.92 (t, 1H), 6.84 (4, IN, 2 8.7 Hz ), 6.52 (t, 1Н), 3.89 (5, ЗН); LC/MS: purity: 9795; MS (m/z): 380 (MN). 7.4.69 M2-(3-chloro-4-methoxyphenyl)-5-fluoro-Ma.- | Analogous to the preparation of 2-chloro-5-fluoro-M4-(12-(M-methylaminocarbonium)aminopyrid-6-1l|- (se)

P-(Memethylaminocarbonyl)nolol-b-yl)-2,4-pyrimidinamine, M2-(3-chloro-4-methoxyphenyl)-5-fluoro-M4-(M1-(M-2,4-pyrimidineliamine) (K927100) methylaminocarbonyl)indole-b-yl|-2,4-pyrimidindiamine is obtained as a result of the reaction M2-b(3-chloro-4-methoxyphenyl)-5-fluoro-M4-(indole-b-yl)-2,4 -pyrimilindiamine and triphosgene followed by quenching with methylamine. LC/MS: purity: 8895; MS (m/z): 441 (MH). 7470 Ma-(2-aminopyrid-6-1l)-5-fluoro-M243- Similar to the preparation M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2- - hydroxyphenyl)-2,4-pyrimidinediamine (3-eM-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4-(2-aminopyrid-6 - (К927083) yl)-5-fluoro-M2-(3-tihydroxyphenyl)-2,4-pyrimidineliamine is obtained as a result of MA reaction. se (2-aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimidinamine and 33-hydroxyaniline. /"Н YAM? (0М5О0-а6): 59.17 (5.15, 9.13 (8, IN), 8.67 (5, IN), 8.08 (4, IN, 1- 3.0 Hn), 7.42 (t, 18), s 7.35 (1.212 7.8 Hz), 7.18 (68, 1), 7.14 (v, IN, 4-72 i), 6.98 (2, 18, 1- 7.8 Go), 6.31 (49,

IN, 1.2 and 6.9 Gy, 6.170, 1H, 2-7.5 Gy), 5.77 (point NN); LC/MS: purity: 10095: MS (mi): PPE (Mn. hall Ma-3-chloro-4-methoxyphenyl)»3-fluoro» Similar to the preparation of 2-chloro-5-fluoro-14х4-(2-(0М) -methylaminocarbonyl)aminopyrid-b-yl|.-

M211-(M-methylaminocarbonyl)indole-b-7,4-pyrimidinamine, M4-(3-chloro-4-methoxyphenyl)5-fluoro-M2Y-(M- « yl|-2,4-pyrimylindiamine (K927094) methylaminocarbonyl) ndol-b-yl|-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-(indol-6-yl)-2,4-pyrimidinediamine and triphosgene with followed by quenching with methylamine. "H NMR (OM5O-46): 4 11.09 (5, IN), 9.70 (9, 1H, 4.2 8

Gy), 9.49 (5, 1H)), 8.18 (9, TA, 13.3 Hn), 7.544, 1, 1-5 8.4 Gy), 7.81 (1, I 27 Hz) , 7.30 s (4, EN, 1-27 Go), 7.15 (5, 1), 6.81 (49, 1H, 2.7 and 9.0 Hyd), 6.72 (46, IN ), Re 1.8 and 5.1

Breed), 6.54 (5, 1H)), 5.74 (8, IN, 19.6 Hn), 3.62 (5, ZNU, 2.77 (d, ZY, 1- 4.5 Hn) ; PHU/MS: ; » purity: 9905; MS (m/zu: 441 (Mn. tA M2-(3-xpor-4-methoxyphenyl)-M442.2" Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl )-5-fluoro-M2-dimethyl-3-oxo-4H-bena|1 oxazine-b- (3-(h-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(3-chloro-4-yl )-5-fluoro-2,4-pyrimidinediamine methoxyphenyl)-Ma-(2,2-dimethylp-3-oxo-4H-benzi 1,4 |oxazin-3-6-yl)-5-fluoro-2,4 - (8927097) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-dimethyl-3-oxo-4H- (o c benz|1,4|oxazin-6-yl)-5-fluoro-4- pyrimidineamine and 3-chloro-4-methoxyaniline. "H NMR (pM50-46): δ 10.60 (5, IN), 9.31 (5, 1HO, 9.08 (5, IN), 8.04 ( 0, 1H, 3" 3.6 Gu, 7.81 (4, 1H, 7- 3.3 Hz), 7.45 (49, 1H, 5: 2.7 and 9.3 Go), 7.23 (da, 1, 7-21 and 8.7 Gy), 7.16 (a, 1H, and: 2.4 Hz), co p 6.93 (d, 1H, 3- 9.0 Hn), 6 ... 7. Al3 MA43,4-dichlorophenyl)-y M2-(2,2-dimethyl-3- | Analogous to the preparation of Ma4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-3-fluoro-M2-oxo-4H-benz(i,5)oxazin-b-yl)-5-fluoro- | I34(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinidiamic, M4-(3,4-2,4-pyrimidinediamine (927059) dichlorophenyl)-M2-(2,2-dimethyl-3-oxo-4H-benzi I Oxazine-b-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-dichlorophenyl)-5-fluoro-dpyrimidinamine and 6-amino-2,2-dimethyl -3-oxo-4H-benzi 1, oxazine. "NN NMR (OM50- du: 5 10.64 (5, 18), 10.10 (5, IN), 9.72 (5, 1H), 8.22 (4, IN, 3- 3.9 Gy ), 8.10 (5, IN), 7.74 (va, 1H, 72 9.0 Gy, 7.52 (d, 1H, 7: 9 Ha); LC/MS: purity: 8995; MS (m /z): 448 (МН). 7.44 М2-(4-chloro-3,5-dimethylphenyl)-М44(3,4- Analogous to the preparation of М4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-М2- ethylenedioxyphenia)-5-fluoro-2,4- (3-(Mi-methylamino)carboninmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(4-chloro-3,5-pyrimidinediamine (8927117) dimethylphenyl)-m4-(3 ,4-ethylenelioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is restrained as a result of the reaction of 2-chloro-Ch4-(3,4-styrenedioxyphenia)-5-fluoro-4-ptyrimidineamine and 4-chloro-3,5-dimethylaniline . "H NMR (PM5O-46): δ 9.16 (v5, 2H), 8.04 (y, 1.» 3.6 Hz), 7.45 (v, 2, 7.25(t, 1H ), 6.80 (a, 1H, 7 8.7 Gy), 4.21 (65, 2H), 2.22 (5, 6H); LC/MS: purity: 9195;

MS (m/z 401 (MN). 74al5 M2-(4-chloro-3,5-dimethylphenyl)-M4-(2,2- Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro- M2-dimethyl-3-oxo-4H-benzi 1,4 oxazin-b- (3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M2-(4-chloro-3,5-yl)-5- fluoro-2,4-pyrimidinediamine dimethylphenyl)-M4-(2,2-dimethyl-3-oxo-4iH-benzyl 1,4|oxazin-6-yl)-5-fluoro-2,4-(К927118) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-dimethyl-3-oxo-4H-benz|/1,4oxazineb-yl)-5-fluoro-4-pyrimidinamine and 4-chloro-3,5-dimethylaniline. "H YAME (0M50-46): 5 10.62 (5, 1H), 9.32 (5, 1H), 9.11 (5, 1 NO), 8.06 (4, IN, Te 3.9 Gi), 7.46 (5, 2H), 7.26 (49.1H, 3-24 and 8.7 Hz), 7.18 (t, 18), 6.89 (0, 1H, /-: 8.7 Hz), 2.20 (in, 6H)), 1.49 (5, NU;

LC/MS: purity: 9990; MS (m/z): 441 (M). 7.476 (3-M4-4(2,2-difluoro-3-oxo-4H- Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2- benz(1,4)oxazine-b- yl)-M2-(2-0h- (3-(M-methylamino)carbonylmethypenoxyphenyl|-2,4-pyrimidinediamine, (E)-M4-(2,2-difluoro-3-methylaminocarbonyl)-2,3» oxo -4H-benz 1,4 |oxazin-b-yl)-M2-(2-(M-methylaminocarbonyl)-2, 3-dihydrobenzofuran-5-dithiarobenzofuran-5-yl|-5-fluoro-2,4-yl |-5-fluoro-2,4-thyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-difluoro-3-pyrimidinediamine (4927049) oxo-AN-benzyl 1.4)oxazin-6-yl)-5- fluoro-4-pyrimidinamine and (4)-5-amino-2-(M-methylaminocarbonyl)-2,3-dihydrobenzofuran. "H NMR (0M50-46): 5 11.96 (in, 1H), 9.48 (5, 1NU, 8.92 (5, 1H), 8.06 (y, IN, 1-- 3.6 Gy), 8.01 (4, TA, 7: 4.5 Hz), 7.56 (t, 18), 7.49 (b5, 15), 7.40 (5, 1H), 7.23 (t, 2H), 6.67 (0, IN, 1 8.7 Gy), 5, 04 (44, 1H, 7: 5.7 and 6.6 Hz), 3.58 (aa, 1 HO), 3.11 (49, 1H, B- 5.7 and 6.6 Gy), 2, 59 (y, ZN, 1 4.5 Ha); LC/MS: purity: 9895; MS (m/zu: 487 (MN). 4-m4-(3-chloro-4-methoxyphenyl)-M2-(2 - Similarly to the preparation of Ma-(3-chloro-4-methoxycarbonylmethyleneoxyphenia)-5-fluoro-M2-si (M,M-dimethylaminocarbonyl)-2,3- (3-(M-methylamino)carbonylmethyleneoxyphenia|-2,4-pyrimidinediamine, Sk)-M4A(3-chloro-4-dihydrobenzofuran-5-yl|-5-fluoro-2,4-methoxyphenyl)-M2-(2-(M,M-dimethylaminocarbonyl)-2,3"dihydrobenzofuran"5-yl1- 5-fluoro-(o)pyrimidinediamine "(K927052) 2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and (1)-5 "amino-72-(M,M-dimethylaminocarbonyl)-2,3-dihydrobenzofuran. "H NMR (0M5O0-4y6): 6 9.24 (5, 1H), 8.98 (5, 10), 8.01 (4, IN, 32 3.3

Gi), 7.74 (8, 1H, 2: 2.4 Hz), 7.64 (04, 1H, 127.1 and 9.0 Hn), 7.49 (5, 183, 7.19 (8 , 1H, 8.7 Hz), 7.104, 1H, 1- 8.7 Gy), 6.64 (0, 1H, y- 8.7 Gy), 5.54 (44, 1H, Te 8.7 and 7.8 Hu), 3.84 (5, ZN), 3.30 (t, 2NU, 3.08 (5, ЗИ), 2.86 (5, ZN); LC/MS: purity: 9395; MS (m/3): 458 (MIN), (Ce) 7.48 (9 Ma43-chloro-4-trifluoromethoxyphenyl)- | Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2- Tech!

М2-(2-(М, Methylaminocarbonyl)-2,3-| 5-fluoro-2,4-trifluoromethoxyphenyl)-M2-(2-(M,M-dimethylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl|-5-pyrimidinediamine (К927053) fluoro-2,4-pyrimidinediamine is obtained in as a result of the reaction of 2-chloro-M4-(3-chloro-4- or trifluoromethoxyphenyl)-5-fluoro-4-pyrimidinamine and ()-5-amino-2-(M,M-dimethylaminocarbonyl)-2,3-dihydrobenzofuran, "H NMR (0M50-46): 5 9.59 (5, 1H), 9.10 s (51NU 8124, 1H, 1- 3.6 Gy), 8.09 (5, 1H), 7.83 ( 54, 1H, 1: 8.7 Hz), 7.48 St, 2), 7.20 (L8, 1H, 2121-84 Hz), 6.67 (4, TN, 3: 8.4 Hz), 5.58 (4, 1H, 72 8.1 Hn), 3.30 (t, 2H), 3.08 (5, ЗН),

Z5 3.86 (in, ZM); LC/MS: purity: 9695; MIS (m/z): 512 (MIN). c 7.4.79 ()-ma-(3-chloro-4-methoxyphenyl)- M2-12- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-12-(M- ( M-methylaminomethylene)-2,3-morpholino)ethyleneoxy |phenyl|-2,4-pyrimidinediamine, as a result of the reduction of ()-M4-(3-dihydrobenzofuran-5-yl-5-fluoro-2,4-chloro-4 -methoxyphenyl)-M2-12-(M-methylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl|-5-fluoropyrimidinlyamine (K927045) 2,4-pyrimidinediamine borane: methyl sulfide is obtained with (-)-M4-( 3-chloro-4-methoxyphenyl)-

M2-(2-(M-methylaminomethylene)-2,3-dihydrobenzofuran-5-yl|-5-fluoro-2,4-pyrimidinediamine. "'H NMR (0M50-46); 5 9.22 (5, 1 ), 8.92 (5, IN), 8.01 (f,1H, 32 3.6 Hz), 7.78 0, 18, 1-30

Hz), 7.64 (t, 1H), 7.43 (05, 1H), 7.16 (49, 1H, 1-: 2.4 and 10.5 Hz), 7.08 (y, 1H, 1: 8.7 Gy), 6.57 (84, IN, 12 VI Hn), 4.77 (t, 1NU, 3.82 (5, ZNU, 3.11 (44, 18, 1- 9.3 and 8.7 Hn), 2.85 (da, TN, 7- - s 7.5 Gyz), 2.66 t, 2H), 2.30 (4, ZN); LC/MS: purity: 9595; MS (m/z): 229M'); 430 (MN). 7.4.80 5-fluoro-M2-|20E)-4(IV, 25, 5K)- Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-m z» menthyloxycarbonyl)-2, 3" (34(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrumidinediamine, 5-fluoro-M2-12(B)- and dihydrobenzofuran-5-yl1-M4-(4-418, 25, 58.)-menthyloxycarbonyl )-2,3-dihydrobenzofuran-5-171-M4-(4-isopropoxyphenyl)-isopropoxyphenyl)-2,4-pyrimidineliamine | 2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M44(4- (8927062) isopropoxyphenyl)-4-pyrimylinamine and 5-amino-(2(K)-(IR, 25, 5K)-menthyloxycarbonyl ) |- 2,3-dihydrobenzofuran.. LC/MS: purity: 9395; MS (m/z: 563 (MN). o 7.4.81 М4-(2,2-difluoro-3-oxo-4Н- Analogous to the preparation of М4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-3-fluoro-М2- Benzy 1,4 |oxazin-b-yl)-M2-(E)AE, |3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4.(2,2-difluoro-3-25, 58) -menthyloxycarbonyl) -2,3-oxo-4H-benz| 1 Poxazin-6-yl)-Mm2-Y2(B)-4(B, 25, 58)-menthyloxycarbonyl)-2,3-kz dihydrobenzofuran-5-1l1-5-fluoro-2,4- lihydrobenzofuran-5- il|-5-fluoro-7,4-pyrimidinediamine is obtained as a result of the reaction 2- -y (Ce) 42) ko 60 b5 pyrimidinediamine (8927063) chloro-M4-(2,2-difluoro-3-oxo-4H-benz | 1,4 |oxazin-b-yl)-5-fluoro-2,4-pyrimidinamine with 5-amino-H(8)-1(1E, 258, 52) methyloxycarbonyl)-2,3-dihydrobenzofuran. LC/MS: purity: 93925; MS (m/z)y: 612 (MN).

Preparation of salts based on bis-VMAg products 7482 Salt of p-toluenesulfonic acid M2-(3,5- Dry reactor with a magnetic stirrer, rubber membrane and feed hole M; dimethoxyphenyl)-M4-(2,2-dimethyl-3-oxo- fill in M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethyl-3-oxo-4H-benz| 1,4 |oxazin-6-yl)-5-4H-benz 1,4| oxazine-b-ip)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (0.220 g, 0.5 mmol) and MeOH (15 mL). To this suspension of pyrimidinediamine (K927070) p-toluenesulfonic acid monohydrate (0.095 g, 0.5 mmol) was added at 0 "C for 2-3 minutes. After adding p-topotoluenesulfonic acid monohydrate, the suspension turned into a clear solution. After stirring the solution for 5 minutes , it is concentrated using a rotary evaporator, and the precipitate is recrystallized with NINEU As: hexanes (1:1:5 ml; by volume) to obtain the salt of p-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2, 2-Dimethyl-3-oxo-4H-benzyl 1,4 (oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine Alternatively, the precipitate is taken up in EOH and precipitated with n-hexanes or ethyl ether to give salts of p-toluenesulfonic acid M2-(3,5-dimetaoxyphenyl)-M4-(2,2-dimethyl-3-oxo-4H-benzi 1 4|oxazine-b-1l)-5-fluoro-2,4-pyrimidinediamine in the form of an amorphous solid. "H NMR (0М5О-46): δ 10.60 (5, 1Н), 10.07 (vv, 1Н), 9.60 (b5, IN), 8.15 (4, 1Н , 1- 5.1 Hn), 7.44 (44, 2H, 34-:1.2 and 6.0 Gy), 7.28 (t, 18), 7.16 (t, 1), 7.10 ( 44, 2H, )- 1.2 and 6.0 Gy), 6.854, 1H, 1- 8.4 Gy), 6.74 (i, 2H, 2.8

Gsh), 6.19 0, 1Н,2- 2.8 Hz), 3.64 (5, 6Н)), 2.289 (5, ЗН), 1.41 (5, 6Н); LC/MS: purity: 10099;

MS (m/z: 440 (MA as the starting base). 7.4.83 Salt of methanesulfonic acid M2-(3,5- Analogously to the preparation of the salt of p-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2,2- dimethoxyphenyl) )-M4-(2,2-dimethyl-3-oxo- benz 1, oxazin-b-yl)-5-fluoro-2,4-methanesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethyl.-3-oxo-4H.pyrimidinediamine (2927071) benz |1,4)oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine is reduced as a result of the reaction M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethyl-3-oxo-4H-benzi 1,Hoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine and methanesulfonic acid. LC/MS: purity: 9825; MS (m/z): 440 (MN"; as the starting base). 7.4.84 Salt of benzenesulfonic acid M2-(3,5- Analogously to the preparation of the salt of p-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2, 2» dimethoxyphenyl)-M4-(2,2-dimethyl-3-oxo-|limethyyl-3-oxo-4H.benzyl 1,4|oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine, salt

AN-benzi 1,4|oxazine-6-12)-5-fluoro-2,4- benzenesulfonic acid M2-(3,5-dimethoxyphenial)-MA-(2,2-limethyl-3-oxo-4H-pyrimidinediamine ( 2927072) benzene 1, Noxin-6-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethyl-3-oxo-4H -benz|1,4|oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine with benzenesulfonic acid. Shk YAM (OM50-46): 5 10.61 (5, 1), 10.00 Ha (65, 1H), 9.57 (Bv, IN), 8.15 (9, 1H, Ge 4.5 Hz ), 7.57 (pt, 2NI), 7.28 (t, ЗН), 7.16 (b, 1), 6.86 (YAN, 1-8, Hz), 7.76 (b5, 18), 6 ,17 (d, IN, I): 2.1 Giv), 3.64 (5, BNO), 1.41 (5, 6H); LC/MS: Ge) purity: 10099; MS (m/z): 440 (MH; original base). 7.4.85 Tihydrochloride M2-(3,5-dimethoxyphenyl)- Similar to the preparation of the salt of p-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2,2-

M442,2-dimethyl-3-oxo-4H-dimethyl-3-oxo-4H-benz| 14 Ooxazin-6b-yl)-5-fluoro-2,4-pyrimidinediamine, hydrochloride YM2- benzo(i, Yaoxazin-6-1l)-5-fluoro-2,4-(3,5-dimethoxyphenyl)-M4- (2,2-dimethyl-3-oxo-4H-benz| I, 4|oxazin-6b-yl)-5-fluoro-7,4-pyrimidinediamine (K927073) pyrimidinediamine is obtained as a result of the reaction M2-(3,5- dimethoxyphenyl)-M4-(2,2- (Che) dimethyl-3-oxo-4H-benz| 1,4 |oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine with hydrogen chloride (4M, dioxane ). LC/MS: purity: 10095; MS (m/z): 440 (MN; as starting base). b 7.4.86 Salt of Ri.-camphorsulfonic acid M2-(3,5- | Analogously to the titration of the salt of p"-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethoxyphenyl)-Ma4-(2,2 -dimethyl-3-oxo- | dimethyl-3-oxo--H-benz | 1,4 |oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine, Ri salt - 4AN-benz ( i, 4oxazine -6-yl)-5-fluoro-2,4-camphorsulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethyl-3-oxo-4H- pyrimidinediamine (2927074) benzi1,oxazine-b -yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethyl-3-okeo-4H-benz| 1,4|oxazine- 6-yl)-5-fluoro-2,4-sem pyrimidinediamine with ОЙ -camphorsulfonic acid. "H NMR (PM 5O-46): 8 10.59 (in, 1H), 10.10 (B5, IN), 9 .65 (B6, EN), 8.17 (y, 1H, 2- 4.5 Hz), 7.27 (t, IN), 7.15 (vv, 1), 6.86 (4, IN, 1" 8.4 so

HB, 6.74(4, 1 H, ze 2, Go), 6.19 (t, 1H), 3.64 (5, 6H), 2.89 (f, 1H, 32 11.7 Hm), 2.66 (t, 18), 2.48 (t, 2H), 2.40 (d, IN, 7: 14.7 Hyd), 2.23 (1, 1H, 7» 3.3 and 18 .3 Hn), 1.94 (t, 1), I.85 (t, ?2NU, 1.41 (5, 6H), 1.25 (t, 2), 1.05 (5, ZNU, 0 ... -toluenesulfonic acid 142-(3,5-dimethoxyphenyl)-iM4-(2,2-"dimethylphenyl)-M4-22,2-dimethyl-3-oxo-dimethyl-3-oxo-4H-benz| 1,4 oxazine- b-yl)-5-fluoro-2,4-pyrimidinediamine, salt of p-4H-benz and ,NHoxazin-b-yl)-5-fluoro-2,4-ltoluenesulfonic acids M2-(3,5-dimethylphenyl)-144 -(2,2-dimethyl-3-oxo-4H-pyrimidinediamine (5927075) benzyl 1,4 |oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction M2- shsh (3.5 -dimethylphenyl)-M4-(2,2-dimethyl-3-oxo-4H-benzyl)-5-fluoro-2,4-s pyrimidinediamine with p-toluenesulfonic acid. "H NMR (PM5O-46 ): 5 19.65 (5, 1H)), 9.95 c (B5, 1NI), 9.40 (B5, 11), 8.13 (4, 1H, 12: 4.8 Gy), 7.45 (4, 2H, 12: 7.8 Gy), 7.26 (t, 1), 7.14 (05, - 18), 7.099, 2H, 1- 7 .8 Hz), 6.89 (4, 1H, 7-8.7 Hz), 6.63 (65, 18), 2.28 (5, Z), 2.16 (5, 6H), " 1 ,0 (5, 6H); LC/MS: purity: 10096; MS (m/z); 408 (MN; as a starting point). 7.4.88 Salt of benzopsulfonic acid M2-(3,5- Analogously to the preparation of p-toluenesulfonic acid salt M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethydphenyl)-M4-(2,2-dimethyl-3-oxo - dimethyl-3-oxo-4H-benzi 1,4 (oxazin-b-yl)-5-fluoro-2,4-pyrimidinedigmine, salt

AN-benz|! 4 |oxazin-6-yl)-5-fluoro-2,4- benzenesulfonic acid M2-(3,5-limethylphenyl)-im4-(2,2-dimethyl-3-oxo-4H-(ee) pyrimidineliamine (2927076) benzyl1,4|oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction M2-(3,5-dimethylphenyl)y-M4-(2,2-dimethyl-3-oxo-4H .benz 4 |oxazin-b-1l)-5-fluoro-2,4-kmshi pyrimidinediamine with benzenesulfonic acid. YUM? (0М50-а6): 6 10.67 (5, 1Н), 1012 -y 7 42) ko 60 b5

What (65, TN), 9.55 (5, TN), 515 (9, 1Н, 7-46 Hz), 7.57 (t, 28), 7.28 (t, 4), 7.11 (in, ЗН), 6.96 (4.1Н, 2-84 Го), 6.66 (65, 1), 1.40 (5, 6Н); RHLMS: purity: 10095; MS (m/z: 408 (MN"; as the starting base). 7.4.89 Salt of p-toluenesulfonic acid M4-(3- Analogous to the preparation of the salt of p-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2,2 - chloro-4-methoxyphenyl)-5-fluoro-M2-(indole-|dimethyl-4H-benzyl)-5-fluoro-2,4-pyrimidinediamine, salt n» b-yl)-2,4-pyrimidinediamine (2927087) toluenesulfonic acid M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-(indole-b-1l)-2,4-pyrimidinediamine is obtained as a result of reaction M4 -(3-chloro-4-methoxyphenial)-5-fluoro-M2-(inlol-b-yl)-7,4-pyrimidinediamine and p-toluenesulfonic acid salts. LC/MIS: purity: 10095; MS (m/iz) : 384 (MH"; as the starting base), 74.90 Salt of p"toluenesulfonic acid M4-(3,4. Analogous to the preparation of salt of p-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2,2- ethylenedioxyphenyl)-5 -fluoro- M2-|3-(M- dimethyl-4H-benz| and ,4-oxazine-3-oxo-6-1l)-5-fluoro-2,4-pyrimidinediamine, salt p. methylamino)carbonylmethyleneoxyphenia|- | toluenesulfonic acid M4-(3,4-ethylenedioxyphevyl)-5-fluoro-M2-(3-(M-2,A-pyrimidinediamine (5927090)) methyl ino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-13-(M-methylamino)carbonylmethyleneoxyphenium|-2,4-pyrimidinediamine and a salt of ptoluenesulfonic acid, "H NMR (DM 50-46): 6 9.99 (b5, IN), 9.79 (y5, IN), 8.14 (4, 1H, 1: 4.8 Gy), 7.97 (bd, IN , 3- 5.1 Gy), 7.44 (40, 2H, 1- 2.4 and 9.0 Hz), 7.25 (t, 1H), 7.14 (t, 58), 6.80 (4, 1, 2: 8.4 Hyd), 0.64 (t. IN), 4.36 (5, NU, 4.22 (5, NO), 2.64 (4, ZN, 3- 4.8 Gy), 2.28 (5,

ZN); LC/MS: purity: 10095; MS (m/z): 426 (MN; as starting base). Synthesis of anilines and products mono 5MAg

TA 2-isopropoxy-5-nitropyridine A solution of 2-bromo-5-nitropyridine (1.0 g, 4.9 mmol), potassium t-butylate (6.9 mL, 6.9 mmol, IM solution in THF), and of isopropyl alcohol (75 ml) is heated at a temperature of 752C for 2 days. The reaction mixture is concentrated in a vacuum, and the precipitate is suspended in water and sonicated at room temperature for several minutes,

The product as a beige solid was collected by filtration. INYAME (SsOSIzh 8 9.06 (d, 2-3.0 Gy, 1H), 8.31 (440, 7- 3.0 and 9.3 Gy, 13), 6.73 (d, 12: 9.3 Hz, IN), 5.43 (Aimei, 125.7 Hz, IN), and 1.37 (y, 7-6.3 Gy, 1H). 7492 5-amino-2-isopropoxypyridine Analogously to the preparation of ethyl 4-aminophenoxyacetate, hydrogenation of 2-isopropoxy-5-nitropyridine is carried out to prevent 5-amino-2-isopropoxypyridine. IN YAM" (SOS): 5 7.65 (9.7-2.7 Hz, IN), 7.01 (49, 2: 3.0 and 8.7 Gy, 1H), 6.54 (4, 1- 9.0 Gy, 1H), 5.13 (dshlie A- 6.6 Hz, 1), 3, 20 (5, 2H), and 1.32 (y, 1- 6.6 Gy, 6H). 7.4.93 2-chloro-5-fluoro-M4-4(2- Analogous to the preparation of 2-chloro-M4-( 3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, isopropoxypyridin-5-1l)-4-2-chloro-5-fluoro-M4-4(2-isopropoxypyridin-5-yl)-4-pyrimidinamine is obtained in sem pyrimidineamine as a result of the reaction of 2,4-dichloro-5-pheorpyrimidine and 5-amino-2-isopropoxypyridine. /H NMR He) (SSZ): 5 8.30 (y, 7-3.0 Hz, NN), 8, 06 (0, 1-21 Hz, 18), 6.81 (b5, 15), 6.75 (0, 1- 9.0 Hz, 1H), 5.27 (dshte, 7- 6.6 Hz, 18), and 1.35 (4.5: 6.6 Hz, 6H). 7.4.94 3-chloro-44(M-morpholino)nitrobenzene A mixture of 2-chloro-4-fluoronitrobenzene (1.36 g, 7.72 mmol) and morpholine (8.0 ml, 90 mmol) is heated at 809C for 3 hours . The reaction mixture is poured into a beaker (150 mL), and the product as a yellow solid is collected by filtration. NMR (SOSIz): 8 (Se) 8.26(a, 1-30 Hn, 1), 8.11 (dd, 2-3.0 and 9.3 Hz, EN), 7.05 (0, 1 -87 Hz, EN), 3.91-3.87 (t,

AN), and 3.23-3.19 (t, 4H). (e") 7.4.95 3-chloro-4-(M-morpholino)aniline To a solution of 3-chloro-244(M-morpholino)nitrobenzene (1.0 g, 4.1 mmol) in ethanol/water (70 ml , 2:1) first add iron powder (1.4 g, 25 mmol), and then MH.SI (0.46 g, 8.6 mmol). The reaction mixture is stirred at room temperature for 10 minutes, then heated at 799 for 1.5 hours. After cooling to Ha! room temperature, the reaction mixture is filtered through Nelite, and the precipitate formed on the filter is washed with methanol. As a result of the concentration of the filtrate in a vacuum

A white solid is obtained which is dissolved in stylacetate and washed with ManSO, (Ge) (89) and brine. The organic layer was dried (Me5O), filtered, and concentrated in vacuo to give the product as a white solid. 1H NMR (SRSI ze 6.98-6.91 (t, H), 6.82 (B5, 1H), 6.67-6.61 (t, 1H), 3.90-3.82 (t, 4H), and 3.02-2.90 (t, 4H). 7.4.96 2-chloro-Ma-g3-chloro-4-04- Analogous to the preparation of 2-chloro-Ma-(3,4-etiphenedioxyphenyl)- 5-fluoro-4-pyrimidinamine, "morpholino)phenyl)|-5-fluoro-4-2-chloro-M4-(3-chloro-4-(M-morpholino)phenyl|-5-fluoro-4-pyrimidinamine is obtained and pyrimidineamine resulting from the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-(M-morpholino) aniline.

NMR (SOSIU 5 8.09 (0, 1- 2.4 Hz, 1Nu 7.75 (8, 7- 3.0 Hu, IN), 7.55 (60, 2- 2.7 and 8.7 Hu , with IN), 7.320, 1-5 8.7 Si, 1H), 6.92 (65, IN), 3.99-3.92 (t, 4H), and 3.21-3.14 (t , 4H). h 7.A97 3-Chloro-4.isopropoxynitrobenzene Analogously to the preparation of 2-isopropoxy-5-nitropyridine, 3-chloro-4- and » isopropoxynitrobenzene is obtained as a result of the reaction of 3-chloro-4-feoroxynitrobenzene with isopropanol and t- potassium butylate. 1H NMR (SOCI3): b 8.26 (8, 1-3.0 g, 1), 8.11 (da, 1-30 and 8.7 Hz, 1H), 6.97 (d, 1 - 8.7 Gy, 1NU, 4.71 (dsipse, 2-2 6.0 Gy, IN), and 1.43 (4, 1- 6.0

Hz, bH). (ee) 7498 3-chloro-4-isopropoxyaniline Analogously to the preparation of 3-chloro-4-(M-morpholino)aniline, 33-chloro-4-isopropoxynitrobenzene is reduced to obtain 3-chloro-4-isopropoxyaniline. other NMR (0M80-4vu: 5 6.80 (0, 12 8.7 Hz, 1H), 6.59 (y, /- 2.4 Gy, IN), 6.43 (49, 12 3.0 . 4, 7-5,7 Gy, EN). 74.99 2-chloro-M4-4(3-chloro-4-isopropoxyphenyl)" | Similarly to the preparation of 2-chloro-M44(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, 5-fluoro-4-pyrimidinamine 2-chloro-M4-(3-chloro-4-isopropoxyphenyl)-5-fluoro- 4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-isopropoxyaniline. /N YAM? (SOS 8 8.04 (4, 22 3.0 Pi, 1H), 7.61 (8.32 2.7 Gy, IN), 7.48 (y, y- 3.0 and 8.7 Hz, 1H)), 6.99-6.93 (t, 2H), 4.52 (dchitek, 12 6.0 Hz, 18), 1.37 (d,3- 6.0 Gy, 68); I9E NMR (282 MHz, SOS): - 158.12; LC/MS: purity: 9495; MS (m/z): 317 (Mn. 74100 5-Amino-2-(MM- Borane-methyl sulfide complex (4.0 ml, 43 mmol) is added to a suspension of 2-HOM,M- dimethylaminomethyl)benzofuran dimethylamino)carbonyl |-5-nitrobenzofuran (1.0 g, 43 mmol) in anhydrous TIF (10 mL).

The reaction mixture is heated under reflux for 3 hours. After cooling, the solvent is removed in vacuo to form a gel-like solid. Cold (0 2 ) methanol (50 ml) is carefully added dropwise, and the resulting mixture is heated at 50 "C for 30 minutes, keeping a clear yellow solution.

The solvent is removed in vacuo, the resulting solid is suspended in methanol (50 mL) and HCl (1.5 mL, 4M in dioxane) is added. After heating at 80 °C for 30 minutes, the solvent was removed under reduced pressure to give an amorphous solid. The solid was dissolved in methanol (20 mL) and ammonia (2M in methanol) was added until the solution became alkaline. After dissolution with dichloromethane, a precipitate (50 ml) is formed. As a result of filtration and concentration, the intermediate 2-(M.Medimethylaminomethyl)-5-nitrobenzofuran is obtained in the form of a yellow oil (1.0 g), which is used without further purification. To the suspension of the intermediate 2-(M ,M-limethylaminomethyl)-5-nitrobenzofuran (1.0 g) in methanol (degassed, 60 ml) is added

Ma»52O4 (0.50 u) and 1095 Ra/C (100 mg). The reaction mixture is stirred in a hydrogen atmosphere for 10 hours. The solid substance is removed by filtration through an auxiliary filter material celite(c), and the precipitate formed on the filter is washed several times with methacol. As a result of concentration, a dark yellow oil is obtained. Product, 5-amino-2-(M,M-dimethylaminomethyl)benzofuran , obtained after purification by column chromatography on silica gel (mobile phase: 095 io 595 methanol (contains 2M MH» udichloromethane). IN' NMR (СО5ОР): 8 7.24 (y, 1Н, 12 8.7 Hn), 6 .91 (41.32 2, Hz), 6.75 (49, 1H, 32 2.4 and 8.7 Hz), 6.65 (5, 1H), 3.87 (5, 2H), 2, 48 (5, 6H).

Reactions of bis-5MAg and subsequent reactions of molten CO) M2-(2-carboxy!-2,3- As a result of the reaction M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(2-methoxycarbonyl-dihydrobenzofuran- 5-yl)-M4-(3-chloro-4-2,3-dihydrobenzofuran-5-yl)-2,4-pyrimidinediamine and lithium hydroxide (SHOH) in THF:H»O trifluoromethoxyphenyl)-5-fluoro -2.4- pyrimidinediamine (8926957) M2-(2-quarboxy1-2,3-dihydrobenzofuran-5-1l)-Y44-(3-chloro-4-trifluoromethoxyphenyl)-5- fluoro-Ge) 2,4-pyrimidinediamine. IN NMR (OM5O-a6): 6 9.62 (5, 1H), 9.14 (8, 1H), 8.11 (ad, 7- 3.6 and 7.5 Hz, 2, 7.81 ( 49, 7- 3.0 and 9.3 Hz, 1), 7.49-7.44 (t, 2H, 7.22 (44, 24 and 8.1 Hz, 1), 6.72 (4, 2-9.0 Hz, 1H), 5.21-5.13 (t, 1 H), 3.48 (4, 1- 10.5 and 15.6 Hz, 1), 3.17 (ad, /- 6.0 and 15.6 Ha, IN); RF/MS: purity: 9895; MS (m/z): 486 (Mn. 7.4.102 (i) Ma-(3-chloro-4-trifluoromethoxyphenyl) - | Similar to the preparation of M4-(3,5-dichloro-4-hydroxypheny)-5-fluoro-im2-|3-014- (Ce) 5-fluoro-M2-(2-(04-2,3-morpholino) carbonylmethyleneoxyphenyl|-2,2-pyrimidinediamine, as a result of the reaction of dihydroxypropylamino)carbonyl-2,3- racemic M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(2-methoxycarbonyl-2,3» b digylrobenzofuran -5-yl|-2,4- lysidrobenzofuran-5-yl)-2,4-pyrimidinediamine and racemic 2,3-dihydroxypropylamine pyrimidinediamine (К926958) obtain a mixture of two racemates IM4-(3-chloro-4-trifluoromethoxyphenyl)-5 -fluoro-M2-124(M-2,3-cyhydroxypropylamino)carbonyl-2,3-dihydrobenzofuran-5-yl|-2,4-pyrimidinediamine, h-

IN NMR (SIZO): 5 8.06 (y, 72 2.4 Hz, 1H), 7.92 (44, 2- 2.4 and 4.2 Gu, IN), 7.58 (ai, 1- 3.0 and 93 Ha, 1H), 7.41-7.37 (t, NU, 7.34-7.29 (t. IN), 7.26-7.19 (t, 1H), 6.82 ( 4, 2-5 8.7 Hz, se 1H), 5.18-5.11 (t, 1H), 3.74-3.66 (t, /H), 3.60-3.52 (t , IN), 3.50-3.42 (t, 2), 3.38-3.35 (t, 1H), 3.21 (44, 1- 7.2 and 13.5 Hz, 1H); 19E NMR (282 MHz, SISOI): -169.15, 60.23; RHUMS: so purity: 9895; MS (m/1): 559 (MH). 7.4.103 (p ma4-(3-chloro-4 -trifluoromethoxyphenyl)- | Similar to the preparation of M4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-IM2-|3-0M- 5-fluoro-M2-(2-(M-2-morpholino)carbonylmethyleneoxyphenyl- 2,4-pyrimidinediamine, (1) M4-(3-chloro-4-hydroxyethylamino)carbonyl-7,3-trifluoromethoxyphenyl)-5-fluoro-M2-H2-(M-2-hydroxyethylamino)carbonyl-2,3- dihydrobenzofuran-5-yl1-2.4-dihydrobenzofuran-5-1p)-2,4-pyrimidinediamine is obtained as a result of the reaction of racemic "pyrimidinediamine (KU26959) 144-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(2 -methoxycarbonyl-2,3-dihydrobenzofuran-5-yl)-2,4-pyrimidinediamine and ethanolamine in. IN 'YAME SVO): 5 8.65-

P t - 8.05 (t, 1H), 7.94-7.90 (t, 1H), 7.68 (a4, 52:30 and 9.3 Gy, 1), 7.39-7.35 (t , 1), 7.31 (ai, 3-2 s 1.2 and 8.7 Gy, 1H)), 6.82 (8.2 8.1 Hz, 10), 5.18-5.10 ( in, 18), 3.64-3.21 (t, 7NuU; 192 NM (282 MHz, SIZO: -169.19, -50.24; LC/MS: purity: 9895; MS (m/z): 529 (MN).

R. 74104 p) ma-(3-chloro-4-trifluoromethoxyphenyl)- | Similar to the preparation of M4-(3,5-dichloro-4-hydroxyphenyl)-5. p-Mm2-(3-(M-p 5-fluoro-M2-(2-0M4-2-hydroxyethyl-M.morpholino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, racemic M4-(3-chloro-4-methylamino) carbonyl-2,3-trifluoromethoxyphenyl)-5-fluoro-M2-(2-methoxycarbonyl-2,3-dihydrobenzofuran-5-1l)-2,4-dihydrobenzofuran»5-yl|-2,4 pyrimidinediamine and M-methylethanolamine obtained as a result of the reaction (orgomide (1) Ma. pyrimidinediamine (K926960) (3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(240M-2-hydroxystil-M-methylaminocarbonyl-

Go | 2,3-dihydrobenzofuran-5-1l|-2,4-pyrimidinediamine. RHLIS: purity: 9595; MS (m/z): 543 (MN. ke 7.4.105 M4-(3-chloro-4-trifluoromethoxyphenyl)-5- Analogous to the preparation of M4-(3,5-dichloro-4-hydroxyphenyl)-3-fluoro-M2 -13-(M-fluoro-m2-12-0M isopropylamino)carbonyl-|morpholino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, (3) M4-(3-chloro-4-. -y 42) 60 b5

2,3-dihydrobenzofuran-5-yl|-2,4-trifluoromethoxyphenyl)-5-fluoro-M2412-(Misopropylamino)carbonia-2.3-dihydrobenzofuran-pyrimidinediamine (KU26961) 5-yl|-2,4-pyrimidinediamine is restrained as a result reactions of racemic M4-(3-chloro-4-trifluoromethoxyphenium)-5-fluoro-M24(2-methoxycarbonyl»2,3-digylrobenzofuran-5yl)-2,4-pyrimidinedismine and isopropylamine. LC/MS: purity: 9496; MS (mu: 526 (MN). 745196 5-fluoro-Ma-(2-isopropoxypyridin-5-yl)-. | Similar to the preparation of M4-(4-chloro-3-methoxyphenia)-5-fluoro-M2-13- (M-

M2413-(M-methylamino)carbonylmstyleneoxypheny)-2,4-pyrimidinediamine, 5-fluoro-M4-2-methylamino)carbonylmethyleneoxyphenyl|- | isopropoxypyridin-5-yl)-M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-2,4-pyrimidinediamine (KU26962) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-42-isopropoxypyridine-5 -yl)-4-pyrimidianamine and 3-(M-methylamino)carbonylmethyleneoxyaniline in isopropanol. YIN YAM? (РМ5О-ав): 6 9.34 (5,

IN), 9.225, 1H)U, 8.60-8.56 (t, 1H)), 8.07 (4, 3.6 Hn, 1H), 8.02-7.92 (t, 2H), 7.36 (05, IN), 7.258, 8.4 Hz, IN), 7.08 (1-81 Gu, 1NU, 6.72 (y, 2- 8.7 Hz, 18), 6.46 ( ad, 5 21 and 8.1 70 Hu, 1NU, 5.17 (amoepea, 7- 6.3 Gy, NN), 4.34 (5, 2NI), 2.63 (9, /- 3.9 Gy ) -5-fluoro-M2- | Analogous to the preparation of MA-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-M2-I34(M-(3chcm-morpholino)carbonylmethyleneoxyphenyl|-2,4-pyrmidinediamine, M4- (3-Chloro-4-hydroxyethylamino)carbonylmethyleneoxy | methoxyphenyl)-5-fluoro-ych2-(3(0M-2-hydroxyethylamino)carbonylmethyleneoxyphenyl |-2,4-pheny)-2,4-pyrimidinediamine (2926963) pyrimidinediamine is obtained in as a result of the resection of M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and ethanolamine. IN NMR (p): 6 7.90 (4.1: 3.3 Hn, 1H), 7.76 (0.2: 3.3 Gy, IN), 7.54 (ai, 7- 2.1 and 8.7 Hz, 1H), 7.34-7.29 (t , 1), 7.17-7.14 (t, 2H), 7.03 (d, 7-8.7 G ts, IN), 6.62-6.56 (t, 1NI), 4.39 (5, 28), 3.87 (5, ZNU, 3.62 0, 1- 5.7 Hz, 2H), 3.40 (i, 12: 5.7 Gy, 2H); 19E NMR (282 MW, SISOU): - 168.65; EX/MS: purity: 9795; MS (m/z): 462 (MAG). 7.4.1198 (7) ma43-chloro-4-methoxyphenyl)-5-fluoro- | Similarly to the preparation of M4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-M2-13-(M-

M2-134(M-2,3-morpholino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, (5) M4A3-chloro-4-dihydroxypropylamino)carbonylmethylene | methoxyphenyl)-5-fluoro-M2-/3-(0M-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl|-2,4-oxyphenyl)-2,4-pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of M4-(3-chloro-4- methoxyphenia)-5-fluoro-Mao" (8926964) (3Z-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and racemic 2,3-dihydroxypropylamine. NMR (0M50-46): 5 5.35 (5, 1H)), 5.23 (5, IN), 8.09 (d, 75 KG,

NU, 7.87-7.78 (t, 2H), 7.70 (49, 122.4 and 9.0 Gy, IN), 7.32-7.27 (t, 29), 7.15- 7.08 (t, 28), 6.48 (ad, 2- 2.4 and 90 Gy, IN), 4.38 (5, 2NI), 3.82 (5, ZNU, 3.55-3, 21 (t, 5H). 3.08-2.98 (t,

ZNU; LC/MS: purity: 9895; MS (mz): 493 (M NN. 7.AL109 M2.M4-bis(4-benzyloxy-3-chlorophenyl)-5- | Similar to the preparation of M2,Ma4-bis(3-hydroxyphenyl)-5-fluoro-2, 4-pyrimidinediamine, with fluoro-2,4-pyrimidinlismine (2926965) M2M4-bis(4-benzyloxy-3-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of le TT TT TT To « 3 reaction 2, of 4-dichloro-5-fluoropyrimidine and 3-chloro-4-benzyloxyaniline. 42 Hz, 1H), 7.76 (44, 12 2 and 5.4 Hz, 2H), 7.62 (ad, 12 2.4 and 9.6 Hz, IN). 7.48-7.29 (t, 11), 7.17 (4, 7 8.7 Gu, 19), 7.09 (4.72 8.7 Hz, 1H), 5.18 (5, 2H), 5.12 (5, 2H) ; LC/MS: purity: 9790; MS (m/z): 562 (MH). 7410 M4-(4-benzypoxy-3-chlorophenyl)-5-fluoro- | Similar to the preparation of M4-(4-chloro-3- methoxyphenyl)-5-fluoro-M2-I3-(M- (Te)

M2-I34(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(4-benzyloxy-3-methylamino)carbonylmethyleneoxyphenyl- | chlorophenyl)-5-fluoro-M2-|3-(M-methylamino)carbonylmethyleneoxyphenyl|-72,4-pyrimidinediamine 2,4-pyrimidinediamine (K926966) is obtained as a result of the reaction of M4-(4-benzyloxy-3-chlorophenyl)- 2-chloro-5-fluoro-4-(e")pyrimidinamine and 3-C(M-methylamino)carbonylmethyleneoxy aniline. IN NMR (0M5O0-ab): 59.64 (5, 1H), 9.535, 1), 8.13 (y, 1-42 Hz, IN), 7.99-7.94 (t, 11), 7 .81 (9, 1-24 Hz, 18), or 7.6784, 31- 2.7 and 8.7 Hz, 1H), 7.48-7.07 (t, 9), 6.52 (44 , 1- 1.8 and 8.1 Hz, IN), 5.18 (5, 28), 4.35 (8 2), 2.62 (y, /- 4.8 Hz, ZN); LC/MS: purity: 9896; MS (m/z): 509(MN). urine tali M4-4(3-chloro-4-methoxyphenyl)-M2-13-(M- Analogous to the preparation of M4-(3,5-dichloro-4-hydroxyphenia)-5-fluoro-M2-13-(M- cyclopropylamino )carbonylmethyleneoxy|morpholino)carbonylmethyleneoxyphenyl/|-2,4-pyrimidinediamine, M4-(3-chloro-4-tho?cophenyl|-5-fluoro-2,4-pyrimidinediamine methoxyphenyl)-M2-13-(M-piclopropylamino )carbonylmethyleneoxyphenyl-5-fluoro-2,4- (8926967) pyrimidinediamine is obtained as a result of the reaction of M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and cyclopropylamine . In

NMR (0M80-y6): δ 9.88 (5, 18), 9.70 (in, 1H), 8.17 (y, 1: 4.8 Hz, IN), 8.06 (y, 1: 3.9 Hn, 18), 7.79-7.76 (t, 1H), 7.65 (44, 1-24 and 8.1 Hz, NO), 7.2257.11 (t, 40), 6 ,57-6,52 (t, IN), 2,32 « (in, 27), 3,82. (5, ZN), 2.69-2.61 (t, 1H), 0.63-0.56 (t, 2), 0.47-0.43 (t, 2H); LC/MS: purity: 9296; MS (m/z): 459 (Mn. 74412 M2-(3-chloro-4-hydroxy-5-methylphenyl)- Similar to preparation 144 44-chloro-3-methoxyphenyl)-5-fluoro-M2-(34(1M - with M443-chloro-4-methoxyphenyl)-5-fluoro-2,4-|methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M24(3-chloro-4-hydroxy-5-pyrimidinediamine (KU26968) methylphenyl) -M4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M44(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinediamine and 3-chloro-p » 4-hydroxy-5-methylaniline. TN YAM (0M50-yr): 6 9.49 (5, 1NU, 9.17 (5, 1H), 8.66 (t, 1H), 8.07 (4.3-4.2 Gu, 1, 7.71-7.62 (t, 2), 7.46 (65, EN), 7.18 (65, IN), 7.09 (9, 1-90, IN), 3.82 (5, ZN), 2.09 (5, ZN); LC/MS: purity: 9595; MS (m/zu: 410 (MN). 7.a4413 M-(3-chloro-4-methoxyphenyl)-M2-(34 (M- Analogous to the preparation of M4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-m2-(3-(M- o cyclobutylamino)carbonylmethyleneoxy | morpholino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4-43- chloro-4-phenyl|-5-fluoro-2.4-pyrimidinediamine methoxyphenyl)-M2-13-(M-cyclobutylamino)carbonylmethyleneoxyphenyl|-5-fluoro-2,4- (K926969) pyrimidinediamine is obtained as a result of the reaction M4-(3- chloro-4-methoxyphenyl)-5-fluoro-M2-co and (3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and cyclobutylamine. In -y 42) 60 b5

NMR (OM5O-46 8 9.52 (5, 1H), 9.37 (in, 1), 8.214, 72 7.8 Hn, 1H), 8.11 (4, 1-3.3 Hz, 1) . , 7.16-7.08 (t, 28), 5.504, 12.4 and 8, Hz, IN), 4.32 (5, 215), 4.24 (a, 8.1 Hz, IN), 3.82 (5, ZA), 2.18-2.05 (t, 2H), 2.00-1.89 (ti, 2H), 1.64-1.53 (t, 2H); RHLMS: purity: 9595; MS (m/z): 4730 МН. 7.4.114 MA442,2-difluoro-3-oxo-4H- Similar to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-4M-benz| 1,4 Zoxazin-6-yl)-M2-(3,5-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, I44-12,2-difluoro-3-oxo-4H-dimethoxyphenyl)-5-fluoro-2 ,4-benz 1,4 |oxazin-b-yl)-M2-(3,5-dimethoxyphenyl)in 5-fluoro-2,4-pyrimidinediamine is obtained in pyrimidinediamine (5926970) as a result of the reaction of 2-chloro-M4-(2, 2-difluoro-3-oxo-4H-benzi I, oxazin-b-yl)-5-(fluoro-4-pyrimidinamine and 3,5-dimethoxyaniline. 1INNMR (M50-a6): 811.92 (5, 1H), 9 .55 (5, EN), 9.09 (5, IN), 8.12 (a, 1- 6.0 Hn, 1), 7.52-7.46 (t, 2H), 7.22 ( 6, 3-87 Hz, INNU, 6.91 (a, 1-24

Hn, 1H), 6.05 (B, 122.4 Go, 1H), 3.61 (5, 6H); 19E YAM? (282 MGu, pM5o-avu «164.56, - 70 76.64; LC/MS: purity: 9895; MS (m/z): 448 (MN). 7.4115 M2-(3-chloro-4-hydroxy- 5-methyphenyl)- Similar to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-4(M-

M442,2-difluoro-3-oxo-4H. methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-43-chloro-4-hydroxy-5-benz(i,oxazin-b-yl)-5-fluoro-2,4-methylphenyl)-M4-(2, 2-difluoro-3-oxo-4H.-benzi 1,4 uxazin-b-1l)-5-fluoro-2,4-pyrimidineliamine pyrimidinediamine (KU26971) is obtained as a result of the reaction of 2-chloro-M4-(2,2- difluoro-3-oxo-4H-benz|1,4)oxazine-6-1l)-5-fluoro-4-pyrimidenamine and 3-chloro-4-hydroxy-5-methylaniline. IN NMR (0М50-а6): 6 11.95 (5, IN), 9.50 (5, IN), 9.00 (5, EN), 8.56 (z, IN), 8.09 (4 , 1- 3.6 Hz, IN), 7.57 (4, 72-24 Hz, 18), 7.49-7.40 (t, 2), 7.24 (5, IN). 7.22-7.19 (t, 1H), 2.07 (5, ZNU; I9E NMR (282 MGy, OM5O- avu -165.46, -76.51; LC/MS: purity: 9496; MS (m/ z): 453 (МН). 7.4.116 Ма4(3-chloro-4-methoxyphenyl)-М2-(3-chloro- | Similar to the preparation of М4-(4-chloro-3-methoxyphenyl)-5-fluoro-М2- 13-0M- 4-methoxy-5-methylphenyl)-5-fluoro-2.4-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3-chloro-4-pyrimylindiamine (K926972) methoxyphenyl)-M2-(3 -chloro-4-methoxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and 3 -chloro-4-methoxy-5-methylaniline. 1H NMR (PM50-46): 5 9.38 (in, 1), 9.255, 1H), 8.094, 1-5 3.6 Hz, 1H), 7.70 (0, 12: 2.4, 1NI), 7.66-7.58 (tya, 2H), 7.33 (4.32 24 Gy, 1H) 7.114, 2- 8.7 Hz, 1), 3 .83 (5, ZN), 3.66 (5, ZN), 2.14 (5, ZNU; RH/MS: purity: 9495;

MS (m/z): 424 (MN). 74417 Ma-(3-chloro-4-isopropoxyphenyl)-5-fluoro- | Similarly to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro- M2-134(M. 142-13-(M- methylamino)carbonylmethyleneoxyphenium |-2,4-pyrimidinediamine, M4-(3-chloro-4 - methylamino)carbonylmethyleneoxyphenyl)- | isopropoxyphenyl)-5-fluoro-M2-|3-(M-methylamino)carbonylmethyleneoxypheni l)-2,4- 2,llurimidinediamine (K926973) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-isopropoxyphene )- with 5-fluoro-4-pyrimylinamine and 3-(M-methylamino)carbonylmethyleneoxyaniline. IN 'NMR he) (PM5O-4v): 6 9.30 (5, 1H), 9.21 (5, 1H), 8.08 (d, 1- 3.6 Ga, 1H), 7.95-7.88 (t, IN), 7.81-7.79 (t, 1H). 7.69 (ai, Re 3.0 and 8.7 Gv, 1H), 7.32-7.28 (t, ZNO), 7.13-7.07 St, 24), 6.49-6.44 ( tp, 1H), 4.57 (diypivy, 7- 6.0 Hz, 1), 4.34 (5, 2NI), 2.63 (y, 1 4.8 Hn, ZN), 1.76 (8 , 7- 6.0 Ha, 5H);

LC/MS: purity: 9995; MS (m/z): 461 (MN). 74118 Ma4-(3-chloro-4-methoxy-5-methylphenyl)-5- Similar to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro-IM2-|3-(M-"se fluoro-M2 -I3-K(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4-(3-chloro-4-methoxy-5-methylamino)carbonylmethyleneoxy|phenyl) | methylphenyl)-5-fluoro-M2-Y3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4- -2,4-pyrimidinediamine (K926974) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4- methoxy-5-(o)methylphenyl)-5-fluoro-4-pyrimidinamine and 3-(M-methylamino)carbonylmethyleneoxyaniline.

YIN YAM? (SOYU; 6 8.01 (d, 2-5.4 Hz, 1H)), 7.60 (0.25 2.4 Hz, IN), 7.40-7.29 (t, 2H), 7 ,10-h- 7.04 (t, 2H)), 6.89-6.84 (t, 1H), 4.38 (5, 2H), 3.79 (5, ЗН), 2.79 (5, ZN), 2.25 (5, ZN); LC/MS: purity: 9655; MC (m): 444MN. c 741119 4-(3,4-dichlorophenyl)-5-fluoro-M2-(indole- | Similar to the preparation of Ma-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-(M-b-yl) )-2,4-pyrimidinediamine (5926975) methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3-chloro-4-methoxy-5-methylphenyl)-5-fluoro-M2-(3-(M-methylamino )carbonylmethyleneoxyphenyl-2,4-(ge)pyrimidinedismine is obtained as a result of the reaction of 2-chloro-MA-(3,4-dichlorophenyl)-5-fluoro-4-nyrimidineamine and b-aminoindole. 7N NMR (SIZO): 5 7, 99 (y, 7- 2.4, 1H), 7.91 (4, 75 3.66

Gy, IN), 7.72 garden, 1- 3.0 and 8.7 Ha, 1H), 7.60 (y, 3-:1.2 Sy, IN), 7.46 (4, 2-8 ,7 Hz, IN), 7.25 (4.159015.1Н), 7.17 (49.3: 30 Hz, 18, 7.06 (yes, re 1.8 Hz, 1 NU, 6.40 ( 9, 2: 3.3 Hz, 1H); 19E NMR (282 MG, SIMOB): -169.48; LC/ME: purity: 9655; MS (m/z): 399 (MN). " 7.4.120 Ш44(3-chloro-4-methoxyphenyl)-5-fluoro-M2- )-2,4-pyrimidinediamine methylamino)carboniamethyleneoxyphenyl|-2,4-tpyrimidinediamine, М4-43-chloro-4- - с (К926976) methoxyphenyl)- 5-fluoro-М2-(indol-b-yl)-2, 4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinediamine and b-aminoindol. (5, 1H), 9.22 (5, 1H), 9.02 (in, 18), 8.05 (4, 1": 3.6 Gu, IN), 7.85 i "4.122, g, 1), 7.81-7.76 (t, ZNU, 7.36 (4, 1- 8.7 Hz, IPN), 7.21 (8.15 1.8 Hn, 18), 7.19- 7.154t, 1), 7.03 (0, 2-87 Hz, 18), 6.30 (85, IN), 3.81 (5, ZNU; RH/MS: purity: 93955; MS (m/zu : ZVOMN. 74421 M4-(2,2-difluoro-3-oxo-4H- Analo method of preparation of 5-fluoro-M44(3-hydroxyphenyl)-M2-Ha-(3-phenyl-1,2,4-oxadiazole-5-obenz) 1,4 |oxazin-6-yl)-3-fluoro-M2-ip)methyleneoxyphenyl)-2,4-pyrimidinediamine, M4-(2,2-difluoro-3-oxo-4H-benz 1,4 |oxazin- 6- "indol-b-yl)-2,4-pyrimidinediamine yl)-5-fluoro-M2-(indol-6-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4" (K926977) (2,2-difluoro-3-oxo-4H-benzi 1,4 |oxazin-b-yl)-5-fluoro-4-pyrimidinamivu and b-aminoinlolol. ko ninaooaotTsVTtTsovTVTvovVTVTZhzhtzhtch2a,,estynnnninn -y (Se) 42) ko 60 b5

InyaMmR (2M5O-a6u: 6 11.91 (5, 1H), 10.83 (5, 1H), 9.48 (5, IN), 8.91 (c, 1H), 8.09 (y , /- 3.6

Gy, 1), 7.84 (Bv, 1), 7.68 (ad, 1- 3.0 and 953 Hz, 18), 7.54-7.51 (t, 1), 7.34 (y , 4-8.7 Gy, 1H), 7.20 (5, IN), 7.18-7.14 (tv, 2H)), 6.32-6.28 (t, 1H); LC/MS: purity: 9879; MS (m/z): 427 (Mn. 7.441122 M4-(3-chloro-4-methoxyphenyl)-M2-Y244M,M» | Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-14-( 3-phenyl-1,2,4-oxadiazole-5-dimethylaminomethyl)benzofuran-3-yl|-5-|ip)methyleneoxyphenyl|-2.4-pyrimidinediamine, M44(2,2-difluoro-3-oxo-4H-benz (1, oxazine-b-fluoro-2,4-pyrimidinediamine (5926978) yl)-5-fluoro-M2-(indol-b-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of ?2-chloro-M4- (3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and 5-amino-2-(M,M-dimethylaminomethyl)benzofuran. /H.NMR (OM 50-46 5 9.27 (5, IN ), 9.15 (5, 1H), 8.06 (y,

Te36GHz, 1H)U, 7.85 (5, 18), 7.79 (b, 1-3.0 Hz, 18), 7.59-7.63 (t, 1H), 7.35 (05, 1H), 7.07 (y, 128.7 Su, 1H), 6.59 (5, IN), 3.83 (5, ЗН), 3.56 (in, 2H), 2.21 (5, 6NU; RH/MS: purity: 9795;

MS (m/zu: 443 (MN. 7.4.123 4-(2,2-diphthar-3-oxo-4H-) Analogously to the preparation of 5-fluoro-Ma-(3-hydroxyphenyl)-m2-144(3-phenyl- i,2,4-oxadiazol-5-benz|1,4)oxazin-6-yl)-M2-12-(M,M-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, MA-(2,2- difluoro-3-oxo-4H-benz 1,4 |oxazin-b-dimethylaminomethyl)benzofuran-3-yl|-5-|yl)-M2-12-(MM-dimethylaminomethyl)benzofuran-5-121-5 -fluoro-2,4-pyrimidinediamine

Fluoride-2,4-pyrimidinediamine (KO26979) is obtained as a result of the reaction of 2-chloro-M4-(2,2-difluoro-3-oxo-4H-benzi 1,4 |oxazin-b-yl)-5-fluoro-4 -pyrimilinamine and 5-amino-2-(N,M-dimethylaminomethyl)benzofuran. LC/MS: purity: 9995; MS (m/z): 483 (MN). ТА М4-(3,4-dichlorophenyl)-М2-12-(М,М- Analogously to the preparation of 5-fluoro-М4-(3-hydroxyphenyl)-Мм2-(4-(3-phenyl-1,2,4- oxadiazol-5-dimethylaminomethyl)benzofuran-5-yl-5-|yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M44(3,4-dichlorophenyl)-M2-12-(M,M- fluoro-2,4- pyrimidinediamine (К926980) dimethylaminomethyl)benzofuran-5-yl1-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-dichlorophenyl)-3-fluoro-4-pyrimidinamine and 5-amino -244M,M- dimethylaminomethyl)benzofuran. /H NMR (SOSI 3): 6 7.99 (05, IN), 7.89 (4, 72 2.4 Hz, 1H), 7.72 (90.72 2.4 Hu, 1NU, 7.43 (4.32 8.7 Hz, 1, 7.40-7.33 (those, 2H), 7.26 (yes, C 1.8 and 8.7

Hn, 18), 6.97 (5, INU, 6.75 (4.3 2.4 Hm, 18), 6.58 (5, 1NI), 3.67 (5, 2H), 2.38 ( 5, 6H); IUE YAM? (282 MG, SOSIZ): "47438; LC/MS: purity: 9495; MS (m/z): 445 (M-1).

Gtal25 МО-(3 chloro-4-methoxyphenyls.M442,2-.00. 1 Analogously to the preparation of 5-fluoro-MA-(3-hydroxyphenyl) M2-(4-(3-phenyl-1,2,4-oxadiazole- 5-difluoro-3-oxo-4H-benzi 1,4oxazin-b-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(3-chloro-4-methoxyphenyl)-M4-(2,2-difluoro- yl)-5-fluoro-2,4-pyrimidinediamine Zoxo-4H-benzyl 1,4 |oxazip-6-1l)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of (8926981) the reaction of 2-chloro-5- fluoro-M4-(2,2-difluoro-3-oxo-4H-benzyl 4|oxazin-6-yl)-4-pyrimidinamine and 3-chloro-4-methoxyaniline. IN YAM (OM5O-yr): 6 12 .07 (5, 18), 10.09 (5, 1H), 9.75 (5,

pH), 8.20 (4.12 42 Gy NN), 7.75 (0, their 2.4 By, NN), 7.52 (b5, 1), 7.44-7.34 (t, 2Н), 7.27 (4,

Sho 1287 g, 1Nu, 7.03 (4, 1-93 Hz, 1NU, 3.77 (5, ZNU; RH/MS: purity: 9690; MS (m/3K 453. se

ТШВШЗШШТЩШШШВР ОО 2 mi Т072020202052-202020-20020020002020-02О0О0203 o 7.4.126 МА4(2,2- dimethyl-3-oxo-4Н- Analogously to the preparation of 5-fluoro-M44(Z-hydroxyphenyl)-M2-14-(3-phenyl -1,2,4-oxadiazole-5" benzyl 1, Doxazin-6-1l)-5-fluoro-H2-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(2,2-dimethyl-3-oxo -4H-benz| and 4 oxazine-(indole-b-yl)-2,4-pyrimidinedismin b-ip)-5-fluoro-M2-(indole-b-yl)-2,4-pyrimylindiamine are obtained as a result of the reaction 2-chloro- (85926982) M4-(22,2-dimethyl-3-oxo-4H-benzi E,oxazin-b-1p)-5-fluoro-4-pyrimidinamine and 6-aminoindole. /H NMR (M5O-4f): δ 10.81 (5, TE), 10.54 (5, IN), 9.24 (v, IN), 8.81 (5, IN), 8.03 ( 4, 7-2 3.3 Go, 1H), 7.81 (65, EN), 7.45-7.38 (p, IN), 7.34-7.31 (t, 2H), 7, 21-7.14 (t, 2H), re) 6.83 (4, 22 9.0 i, 1H)), 6.28 (8, 12 2.4 Hz, 1H), 1.38 (5, ZNU; LC/MS: purity: 9895; MS (m/z): 49 (ME). (e") 7.4.127 M442,2-difluoro-3-oxo-4H- Similar to the preparation of 5-fluoro-M4-4 (3-hydroxyphenyl)-M2-14-(3-fevyl-1,2,4-oxadiazol-5- benzyl I.oxazin-6-yl)-Mm2-12-(M,M-ylumethyleneoxyphenyl|-2,4 -pyrimidinediamine, M4-(2,2-difluoro-3-oxo-4H-benz(1,4 oxazine-b- or dimethylaminocarbonyl)-2,3-ide) Mm2-(2-(M,M-dimethylaminocarbonyl)- 2,3-dihydrobenzofuran-5-yl|-5-fluoro-2,4-dihydrobenzofuran-5-yl1-5-fluoro-2,4" pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-lifluoro -3-ocoo-4H- with pyrimidinediamine (K926983) benzyl "oxazin-b-yl)-5-fluoro-4-pyrimidinamine and 5-amino-2-(M,M-dimethylaminocarbonyl)-2,3-dihydrobenzofuran. IN YaMe (OM5O0-46): 6 12.09 (5, 1H), 19.15 (8, 180, 9.59 (5, EN), 8.15 (a, 32: 3.9 Hz, 1H), 7.52-7.39 (t, ZNU), 7.26 (0.42 8.7 Gy, IN), so 7.13 (4, 1-5 8.4 Gy, 1H), 6.59 (4, 12 8.7 Gu, 18 ), 5.64-5.57 (t, 1H), 3.43-3.27 (t, 2H)), 3.06 (5,

ZNU, 2.85 (5, ZN); LC/MS: purity: 9695; MS (m/z): 501(M NU. 74128 Mma4-(2,2-difluoro-3-oxo-4H-) Similar to the preparation of 5-fluoro-MA-(3-hydroxyphenyl)-M2-(4-(3- phenyl-1,2,4-oxadiazole-5-benzi 1,4 oxazine-b-1l1)-5-rtor-M2-(3-yl)methyleneoxyphenyl1-2,4-pyrimidinediamine, M4-(2,2-difluoro - 3-oxo-4H-benz 1, Zoxazin-b-methoxy-5-trifluoromethylphenyl)-2,4-yl)-5-fluoro-M2-(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine is obtained in « pyrimidinediamine (K926984) as a result of the reaction of 2-chloro-M4-(2,2-difluoro-3-oxo-4H-benzi I 4 |oxazin-6-yl)-5-fluoro-4-pyrimidinamine and 3-methoxy- 5-trifluoromethylaniline. 1H NAM (FM5O-yf): 6 11.92 (5, 8 s 1H), 9.61 (5, 1H), 9.50 (5, 1NH, 8.18 (d,3- 3 ,6 Hn, 1), 7.65 (5, 1H), 7.59 (5, 1NU, 7.48-7.41 (t, 2H), 7.228, 15 8.7 Hz, IN), 6, 71 (vv, IN), 3.70 (5, ZNU; ISE NMR (282 MHz, OM5O-af): - 163.55, -76.50, -61.83; "purity: 9895; MS (m/ z): 486 (MH). "z 63.55, -76, 61.83; LC/MS: 9895; MS (m/z): 486 (MH n 7.4.129 12-(3,5-dichlorophenia) -M4-(2,2-lifluoro-3- | Similar to the preparation of 5-fluoro-Ma44(3-hydroxyphenyl)- M2-(4-(3-phenyl- 1,2,4-oxadiazole»5-oxo-4H-benz(! Eoxazin-b-yl)-5-fluoro- | yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(3,5-dichlorophenyl)- M4-(2,2-difluoro-3-oxo-2.4-pyrimidinediamine (K926985) A-benz(1,4|oxazin- 6-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-difluoro-3-oxo-4H-benz| 1,4 |oxazin-b-yl)- of 5-fcor-4-pyrimidinamine and 3,5- (ee) dichloroaniline, IN YAM" (PM5O-ar) 6 11.95 (05, 1), 9.65 (0, 1- 3.3 Gy, 2H) , 8,19 (y, 1-39

Hz, 1H), 7.71 (b, 25 1.8 Gu, 2H), 7.41-7.35 (t, 2H), 7.27 (y, 12: 9.3 Hz, 1H), 6 .99 (6, 15: 1.8 Hn, ko -y (Se) 42) ko 60 b5

1n); 19E NMR (282 MG, VM5O-46): -153.24, -76.23; LC/MS: purity: 9296; MS (m/z): 457 (mM).

Al M4-(3-chloro-4-(M-morpholyvo)phenyl-M2- | Similar to the preparation of 5-fluoro-Ma4-(3-hydroxyphenyl)-m2-144(3-phenyl-1,7,4-oxadiazole- 5-(3,5-dimethoxyphenyl)-5-fluoro-2,4-yn)methyleneoxyphenia-7,4-pyrimidinediamine, M4-(3-chloro-4-(M-morpholine)phenyl|-5-fluoro-pyrimidinediamine (2926986) M2-(3,5-dimethoxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-(M-morpholino)phenyl|-5-fluoro-4-pyrimidinamine and 3,5-dimethoxyaniline

NMR (0M50-46): 6 9.80 (08, 1H), 9.53 (05, TO, 8.16 (y, 15 4.2 Hz, 1H), 7.78-7.71 (t, 28), 7.194, 12 8.7 Ha, IN), 6.81 (5, 2НУ6.16-6Л1 (t, 1), 3.75-3.71 (t, 4Н), 3.63 (z, 5H)), 2.96-2.91 (t, 4H); LC/MS: purity: 9595; MS (m/z); 460 (MN). 7.4.131 m4-(3-chloro-4-0M-morpholino)phenyl|-5- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-m2-14-(3-phenyl-1,2,4- oxadiazole-5-fluoro-M2-(3-methoxy-5-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M4-|3-chloro-4-0M-morpholino)phenyl|-5-fluoro»trifluoromethylphenyl)-2 ,4- M2-(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine is restrained as a result of the reaction pyrimidinediamine (K926987) 2-chloro-M4-|3-chloro-440M-morpholino)phenyl-5-fluoro-4 -pyrimidinamine and 3-methoxy-5-trifluoromethylaniline. 1NYMe (рМ50-а5): 6 9.53 (5, 1H)), 9.45 (5, IN), 8.15 (d, 2- 3.6 Gv, 1), 7.77-7.73 (t, 2H), 7.64-7.57 (t, 21), 7.10 (4, 1: 8.7 Hz, 1H), 6.72 (65, 1H), 3.76-3.70 ( t

TN), 2.95-2.91 (t, 4H); 192 NMR (282 MHz, OM8O-y5); 163.57, -61.62; LC/MS: purity: 9995; MS (m/z): 498 (МН), 7.4.132 Salt of p-toluenesulfonic acid M4-(3- Analogously to the preparation of p-toluenesulfonic acid salt M2-(3,5-dimethoxyphenyl)-M4-(2,2-chloro-4 -methoxyphenyl)-5-fluoro-M2-(3-4(M- | dimethyl-4H-wenzi I, 4-oxazin-3-oxo-6-yl)-5-fluoro-2,4-pyrimidinidiamine, salt p - methylamino)carbonylmethyleneoxyphenyl-|toluenesulfonic acid M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-13-0h-7.4-pyrimidinediamine (8926989) methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of reaction M4 -(3-chloro-4-methoxyphenyl)-5-fluoro-M2-|340M»- methylimino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine and p-toluenesulfonic acid monohydrate. TN YAM (0М50-ав): 5 9.91 (B5, 1), 9.65 (B5, 1Н), 8.16 (d, 12: 4.5

Ty, IN), 8.02-7.94 (t, 1H)), 7.78 (d, 22: 2.7 Gy, 1NU, 7.64 (dy, 1: 2.7 and 90 Hz, 1 ), 7.45 (d, 1-5 8.1 Gy, 2NU, 7.22-7.06 st, 6H), 6.63-6.56 (,t, 1H), 4.34 (v, 2H) ), 3.83 (5, ZN), 2.63 (y, 1-5 4.5

Hz, ZN), 2.28 (in, ZN). 7.4.133 Mm4-(3-chloro-4-methoxyphenyl)-M2-(3,5- Similar to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-(M-dichlorophenyl). - 5-fluoro-2,4-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3-chloro-4-pyrimidinediamine (KU26990) methoxyphenyl)-M2-(3,5-bichlorophenyl)-5-fluoro- 2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-Ma-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyramidinamine and 3,5-lichloroaniline. 1Н МАМР (ОМ5О- 4): 5 9.68 (5, 1Н), 9.53 (in, IN), 8.16 (4, 7- 3.9 Hz, 1 Н), 7.69 (4, 12 1.8 Gy, 2H), 7.66-7.58 (t, 2H), 7.13 (0, 39.3 Hz, 18, 7.01 (5-21 Gy, EN), 3.83 (5, ZN); LC/MS: purity: 9756; MS (m/z): 415 (MH). Ge) 7.А4зА M (3-chloro-4-methoxyphenyl)-М2-(3,5- Anapogic preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-(M-dimethylphenyl)-5-fluoro-2,4-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinedimine, I44-(3 -chloro-4-pyrimidinediamine (K926991) In methoxyphenyl)-Mm2-(3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-methoxyphenyl) )-5-fluoro-4-pyrimidinamine and 3,5-dimethylaniline. TN NMR (0M50-465): 5 10.10 (in, 114), 9.79 (in5, 1H), 8.21 (0, 224.8 Hz, IN), (Te 7.71(4,in :2.4 Hz, 1), 7.594, 7-24 and 950 Hz, 10), 7.14 44.4: 950 Hz, 10), 7.09 (65, 28), 6.65 (5, 1H ), 3.85 (5, ZNU, 2.16 (5, 6H); LC/MS: purity: 9995; MS (m/z): 374 (MH). He 7.441135 M4-(3-chloro-4-methoxyphenyl) -5-fluoro-M2- | Similar to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-(M-(3-methoxy-5-trifluoromethylphenyl)-2,4-methylamino)carbonylmethyleneoxyphenyl |-2,4-pyrimidinediamine, M4-(3-chloro-4-pyrimidinediamine (KU26992) methoxyphenyl)-5-fluoro-1h2-(3-methoxy-3-trifluoromethanephenyl)-2,4-pyrimidinediamine and are obtained as a result of the reaction 2-chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and 3-methoxy-5-trifluoromethylaniline. IN yam" (OM50-46): 69.52 (5.180), se 9 ,40 (5, NN), 8.14 (8, 13.9 Hz, 19), 7.72 (4, 3: 2.4 Hz, IN), 7.68 (4th, 1- 2.7 and 9, 0 Hz, 1), 7.64-7.60 (t, 1), 7.59-7.55 (t, 1H), 3.84 (5, ZNM), 3.72 (5, ZN); LC/MS: purity: 9596; MS (ee) (m/zu: 444 (MN). 7.4.136 Mma4-(3-chloro-4-methoxyphenyl)-5-fluoro -M2- | Similar to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-(3-(M-(3,4,5-trimethylphenyl)-2,4-methylamino)carbonylmethyleneoxyphenium|-2,4-pyrimidinediamine . -chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and 3,4,5-trimethylaniline. NR NMR (OM5O-4f): δ 9.23 (65, 1H), 8.91 (b, 1 ), 8.04 (y, /- 3.6 Gv, 1H), 7.78-7.66 (t, 2H), 7.22 (v, 2H), 7.07 (d, 1-2 8 ,7 Hz, TN), 3.83 (5, ЗН)), 2.12 (5, 6Н), 2.03 (5, Шщ

ZN); RHLMS: purity: 9895; MS (m/z); 388 (MN). c 7.4.137 M4-(2,2-dimethyl-3-oxo-4H. Similar to the preparation of Ma-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-(M-n benz|1, oxazine) -b-yl)-5-fluoro-M2-(3,4,5-|methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidineliamine, M4-(2,2-dimethyp-3-oxo- and 2 trimethylphenyl)-2 ... M4-(2,2-dimethyl-3-oxo-4H-benz| and 4|oxazin-b-yl)» of 5-fluoro-4-pyrimidinamine and 3,4,5-trimethylaniline, IN YAM (0М50-а6) :6 10.57 (5, 1), 9.24 (5, IN), 8.78 (5, 18), 8.02 (4, 4- 3.9 Hz, 1H), 7.31 (46 , 7- 2.1 and 8.4 Hz, 1H), 7.26-7.22 (t,

ZI), 6.86 (4, 7-8.7 Gu, 1 H), 2.11 (5. 6H), 2.02 (5, ZNU, 1.40 (5, 6H); LC/MS: purity: 9995; (ee) MS (mii); 422 (MH). 5-dimethoxyphenyl)-2,4-pyrimidinediamine -y 42) 60 b5 p purity: 97 55; MC (mass/charge): 455 (MN). 7.3.1122 M, m4-bis(3-hydroxyphenyl)-6-phenyl-2,4- | Similar to the addition of M2,M4-bis(3,4-ethylenedioxyphenyl)-5-phenyl-2,4-pyrimidinediamine (K925812) to pyrmidinediamine, the reaction between М2,M4-bis(3-hydroxyphenyl)-b-chloro-2,4 - pyrimidinediamine and phenylboronic acid with the formation of 142,M4-bis(3-hydroxyphenyl)-6-phenyl-2,4-pyrimidinediamine. PH/MS: retention time: 22.13 min.; purity: 90 95; MS (mass-charge): 371 (MN. 7.3.123 M2-(3-aminocarbonylmethyleneoxyphenyl)- | As a result of hydrolysis of M2-(3-cyanomethyleneoxyphenyl)-M4-(3,4-ethylenedioxyphenyl)-5-fluoro- 44( 3,4-ethylenedioxyphenyl)-5-fluoro-2,4-2,A-pyrimidinediamine is formed M2-(3-aminocarbonylmethyleneoxyphenyl)-yM4-(3,4-pyrimidinediamine (K926747) ethylenedioxyphenyl)-5-fluoro-2,4 -pyrimidinediamine. LC/MS: retention time: 16.76 min.; purity: 93 95; MS (mass charge): 412 (Mn. 7.311124 M2,m4-bis(3-sodiumphenoxy)-5-fluoro-2,4 As a result of the reaction of M2,M4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine with two pyrimidinediamine (K926461) equivalents of sodium methoxide in methanol, we obtain the desired compound M2.M4-bis(3-sodiumphenoxy)- 5-fluoro-2,4-pyrimidinediamine." I NMR (00: C: 7.65 (vi, 1H), 7.00-6.90 (t, 215), 6.71 (t, 2), 6 ...

Hz CE NMR (020): -47016; LC/MS: retention time: 15.68 min.; purity: 9990; MS (mass/charge: ЗИЗ (МН). 7.3.1125 5-fluoro-M4-(3-hydroxyphenia)-M2-(4- As a result of the reaction M2-(4-cyanomethyleneoxyphenyl)-5-fluoro-MM-(3 -tihydroxyphenyl)-2,4-(1,4,5,6-tetrahydro-2-pyrimidinediamine and NS in stanol, and then 1I,3-disminepropane from methanol at 100 2, pyrimidyl)methyleneoxyphenyl-2,4. 5 is formed -fluoro-Ma4-(3-hydroxyphenyl)-M2-144(1,4,5,6-tetrahydro-2-pyrimidinediamine (2945169) pyrimidine)methyleneoxyphenyl|-2,4-pyrimidinediamine, IN YAM? (C0300):5 2.05 (r. 1-5.7

Hn, 2NU, 3.49 (b, 2: 5.7 Gy, ZNU, 4.84 (5, 2H), 6.56 (440, 122.1, 3.6 1 5.4 Hn, IN), 6.93 (0, 7 9.0 Hz, 2), 7.11-7.13 (t, 2H), 7.21 (t, IN), 7.55 (4, 1-: 9.0 Hz , ZNU, 7.87 (4.3-3.9 Gy, 18); 192 YAM" (282 MGo, SIZO: 5 -168.66; RH/MS: duration of detention: 12.77 min.; purity: 97 .6195; MS (mass/charge): 409.08 (MH. 7.311126 5-fluoro-M4-(3-hydroxyphenyl)-M2-(4- As a result of the reaction between M2-(4-"cyanomethyleneoxy)phenyl|-5 -fluoro-M4-(3-hydroxyphenyl)-

K4A,4-dimethyl-3-oxazoline-2-2,4-pyrimidinediamine and 2-amino-2-methylpropanol form 5-fluoro-M4-4(3-yl)methyleneoxy M2-(4-((4,4-dimethyl-3-oxazolin-2-yl)methyleneoxy|phenyl)-2,4-pyrimidinediamine (K926702) pyrimidinediamine. "H NMR (SOCI"): (1 7.67 (0, 1H, 3-- 3.6 Go), 7.37 (6, 1H, 1- 2.4 yu), 7.346, 2H, 1:90Gsh, 714 1H, 72 8.1 Gy), 6.94 ( re, 1H), 6.90 (8, 2H, 15 9.0 Hn), 6.78 (dd, 1H, 7- 2.4 and 8.4 Hz), 5.74 (a, IN, in 3 ,0 i), 6.62 (44, IN, 7- 1.2, 2.4, and 8.4 Hz), 4.67 (5, 2H), 4.02 (5, 2), 1, 25 (5.6N); "EE NMR (SOSI,)u; "47399; LC/MS: retention time: 13.82 min.; purity: 9895; MS (mass/charge): 425 (МА2Н). 7.3L127 Ma-(3-carboxy-4-hydroxyphenia)-3-fluoro- | As a result of the reaction of a mixture of equimolar particles of 2-chloro-Ma-(3-carboxy-4-hydroxyphenyl)- with 7 o

M2-13-stoxycarbonylmethyleneoxyphenyl|- | 5-fluoro-4-aminopyridine and 3-ethoxycarbonylmethyleneoxyniline in MeOH in a tube of high 2,A-pyrimidinediamine (K950290) pressure at a temperature of 1107C for 24 hours, or in an EIUN with microwave heating to 1757C for 10-20 minutes. with subsequent water treatment, we obtain M4-(3-hydroxycarbonyl-4-tihydroxyphenyl)-5-fluoro-M2-|3-ethoxycarbonylmethyleneoxyphenia|-2,4-pyrimylindiamine. LC/MS: purity: 97.85; MS (mass/charge): 443.20 (MN. 7.3.1128 7M4-(3-carboxy-4-thiproxyphenyl)-5-fluoro- | As a result of the reaction between M4-(3-carboxy-4-hydroxyphenyl)-5 -fluoro-M2-I3- (Ce)

M2-II3-carboxymethyleneoxyphenyl-2,4-ethoxycarbonylmethyleneoxyphenyl-2,4-pyrimylindiamine (0.1 g) and (2OH (10 equivalents) pyrimidinediamine (K950291) in MeOH:water (1:1, v/v) for for one hour at room temperature, followed by treatment with an aqueous solution of NS, a dry residue is formed. 2,4-pyrimidinediamine. LC/MIS: purity: 91.59; MS (mass/charge): 415.16 (MH). 7.311129 Ma-3-methoxycarbonyl-4-hydroxyphenyl)- | Solution M4-(3-carboxy-4-hydroxyphenyl)-5-fluoro-M2-| 3-ethoxycarbonylmethyleneoxyphenyl 5-fluoro-M2-3-ethoxycarbonyl of 2,4-pyrimidinediamine is treated with a 4 M solution of HCl in dioxane from dry MeOH. A mixture of methyleneoxyphenyl|-2,4-pyrimidinediamine | stirred for one hour at 227C, then evaporated to dryness and purified according to (8950293) using flash chromatography on silica gel to obtain a dry white residue M4-(3-methoxycarbon-4-hydroxyphenyl)-5-fluoro-M2-|3-ethoxycarbonylmethyleneoxyphenyl |-2,4-pyrimidinediamine. "H NMR (PM50): C 10.39 (5, IN), 10.13 (5, 1H), 8.22 (F,1H, 1-53 Go), 7.964, 1H, 32.4 Hz), 7.71 (49.3 - 24.90 Hz, 18), 6.95-7.11 (t, Z), 6.51 (t, 1), 4.56 (v, 21), 5.09 (9.4: 7.2 Gy, 2NU, 3.72 (5, 3), 1.14 (i, 1-7.2 Hz, ZN); LC/MS: purity: 96.895;

MS (mass charge: 457.25 (MH). " 7.311130 M4-(4-methoxy-3,4-dihydro-2H-1- As a result of the reaction of a mixture of equimolar particles of 2-chloro-M4-(4-methoxy-3,4 -dihydro-2H-1-bezopyran-6-ip)-5-fluoro-M2-13-benzopyran-6-yl)-5-fluoro-4-aminopyridine and 3-ethoxycarbonylmegyloxyaniline in ЕУН ethoxycarbonylmethyleneoxyphenyl|-2,4- upon microwave heating to 1757 for 10-20 min, followed by aqueous treatment with pyrimidinedimine (K950294), we obtain M4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-M2 -(3-ethoxycarbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine. LC/MS: purity: 92195; MS h z" (mass/charge. 469.26 (MH). p 7.3.L131 M444-methoxy-3,4-dihydro -2H-1- As a result of the reaction of a mixture of equimolar particles of 7-chloro-M4-(4-methoxy-3,4-dihydro-2H-1-benzopyran-b-1l)-5-fluoro-MO-13-benzopyran-b -yl)-5-fluoro-4-aminopyridine and 3-ethoxycarbonylmethyleneoxyaniline in MeOH in methoxycarbonylmethyleneoxyphenyl)!-2,4- | a high-pressure tube at a temperature of 1107 for 24 hours followed by aqueous pyrimidineliamine (K9502 95) we obtain M4-(4-methoxy-3,4-digyho-2H-1-benzopyran-b-iz)-5-fluoro-M2-I|3-so methoxycarbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine. LC/MS: purity: 87.60; MS (mass/charge; 455.26 (MN).

I" b 7.3.11372 M4-(4-ethoxy-3-4-dihydro-2H-1- Solution M4-(4-ethoxy-3,4-dihydro-2H-1-benzopyran-b-yl)-5-fluoro -M2-Y3- benzopyran-6-yl)-5-fluoro-Mm2-13-0M- ethoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine in VN is treated with -42) 60 b5 methylamino)carboniummethyleneoxyphenyl|- | with methylamine hydrochloride, The mixture is stirred for 4 hours at a temperature of 2,A-pyrimidinediamine (K950296) 1007C, evaporated to dryness and purified by flash chromatography on silica gel to form a white dry residue M4-(2-ethoxy-3,4-digylro-?H-1-benzopyran- b-yl)-5-fluoro-

M2-13-4M-methylamino)carbonylmethyleneoxyphenyl!-2,4-pyrimidineliamine. LC/MS: purity: 87.45; MS (mass/charge: 468.29 (MN). 7.311133 Ma-(4-carboxyethyleneoxyphenyl)-z-fluoro- | As a result of the reaction of a mixture of squimolar particles of 2-chloro-M4-(4-carboxyethyleneoxyphenyl)-

M2-Y34(M-5-fluoro-4-aminopyridine and 3-(M-methylamino)carbonylmethyleneoxyniline in MeOH in methylamino)carbonylmethyleneoxyphenyl|- | in a high-pressure tube at a temperature of 110 for 24 hours or in EUN with 2.4-pyrimidinediamine (K950344) microwave heating to 1757 for 10-20 min. with subsequent water treatment, we obtain М4А-(4-carboxyethyleneoxyphevyl)-5-fluoro-М2-13-(М-methclamino)carbonylmethyleneoxypheni|-2,4-pyrimidinediamine. PH/MIS: purity: 97.85; MS (mass/charge: 456.32 (MN). 7.3.1134 Mma4a4(2,3-dihydro-4-benzipyranon-6-yl)-5- | Solution M4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-M2 -(3-(M-fluoro-M2-(3-(M-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine in ТОН methylamino)carbonylmethyleneoxyphenyl|- | (trifluoromethanesulfonic acid) is heated to 100-C for 2 hours. As a result, 2 . methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine LC/MS: purity: 92.29;

MS (mags/charge. 435.95 (My). 7.3.1135 ma-(4-methoxycarbonylethyleneoxyphenyl)- | Solution M4-(4-carboxyethyleneoxyphenyl)-5-fluoro-M2-|3-(m- 75 5-fluoro -m2-|3-(M- methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine in dry MEON methylamino)carbonylmethyleneoxyphenyl|- | treated with a 4 M solution of HCl in dioxane. The mixture is moved for an hour at 2,4-pyrimidinediamine (KU50346) 22, evaporated to dryness and purified by flash chromatography on silica gel to obtain a white dry residue M4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-

M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidineliamine. LC/MS: purity: 85.25; MS (mass/charge): 468.01 (MNU. 7.3.1136 144-(4-hydroxyphenyl)-5-fluoro-M2-13-(M- As a result of the reaction of M4-(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro -M2-I3-(1M- methylamino)carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenyl li-2,4-pyrimidinediamine and BION (10 equivalents) in 2,4-pyrimidinediamine (K950347) MeoNg:water (1:11, v/v) during 1 hour at room temperature, followed by treatment with an aqueous solution of NS, a pale yellow residue is formed. )-2,4-pyrimidinediamine. LC/MS: purity: 94.75; MS (mass/charge) in: 382.03 (MH), 7.1 and 37 Ma-(2,3-dihydro-4-oxime-benzipyran- b- As a result of the reaction of the mixture M4-4(2,3-dihydro-4-benzipyranone-6b-1l)-5-fluoro-M2-H/3-4(4-yl)-5-fluoro-Mm2-13- (M-methylamino)carbonylmethyleneoxyphene l|-2,4-pyrimidinediamine and hydroxylamine (20 and 29 methylamino)carbonylmethyleneoxyphenyl|. | equivalents) in pyridian at temperature Uri 227 for 16 hours followed by aqueous Ge) 2,4-pyrimidinediamine (KU50348) treatment gives a white dry residue M4-(2,3-dihydro-4-oxim-benzipyran-b-yl)-5-fluoro-M2-I34 (M-methylamino)carbonylmethyleneoxyphenyl.2,4-pyrimidinediamine, LC/MS: purity: 89.59; MS (mass/charge): 451.00 (Mn. 7.311358 Mea-(4-hydroxy-3,4-dihydro-?H-1- Solution M4-(2,3-dihydro-2-benzipyranon-5-yl) -5-fluoro-1h2-13-0h- benzopyran-b-yl)-5-fluoro-IM2-(3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in dry MEON (Te) methylamino)carbonylmethylene is treated sodium cyanoborohydride. The mixture is stirred for 1 hour at 22", oxyphenyl-2,4-pyrimidinediamine is evaporated to dryness and purified by flash chromatography on silica gel to give (85950349) a white dry residue M4-(4-hydroxy-3,4-dihydro- 2H-1-benzopyran-b-yl)-5" (e) fluoro-M2-I3-(M-methylamino)carboniamethyleneoxyphenyl|-2,4-lyrimidinediamine. NMR (0M50): 0 9.19 (5, IN ), 9.09 (5, 18), 8.03 (4, 1H,, Re 2.4 Hz), 7.28-7.93 (t, 58), 7.07 (IN, "-- - 72), 6.71 (9.1, 7.2 Hz), ba (ad, 1, 1-26, 7.2 Hz), 5.31 (a, 15.1 - 5.1 Hz), 4 ,14- 4.59 (t, ЗН), 4.30 (5, 2НИ), 2.63 (y, ЗН, 72: 4.8 Gy), 1.82-2.03 (t, 2Н); LC/MO: purity: 93.39; MS (mass charge): 440.15 (MH). se 7.3.1139 4-(2,3-dihydro-4-O-methyloxime- B result those reactions of M4-(2,3-dihydro-4-benzipyranone-b-1l)-5-fluoro-M2-134(M.

From benzypyran-b-yl)-5-fluoro-M2-|30M-methylamino)carbonylmethyleneoxyphenyl|-2,4-thyrimidinediamic and methoxyamine (29 (ge) methylamino)carbonylmethylene equivalents) in pyriline at 22" for 16 hours with the following aqueous treatment with oxyphenyl|-2,4-pyrimidinediamine gives a white dry residue M44022,3-dihydro-4-oxim-benzipyran-b-yl). 5-fluoro-M2-(3- (5950356) (M-methylamino)carbonylmethyleneoxyphenyl|- 2,4-pyrimidinediamine, LC/MS: purity: 85.595; MS (mass/charge): 465.10 (MH). 7.311540 Ma4(4-amino-3,4-dihydro-2H-1- Mixture of Ma-(4 -azido-3,4-dihydro-211-1-benzopyran-o-yl)-5-fluoro- M2-(34(M" « benzopyran-6-hl)-5-fluoro-M2-13-(M- methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine and PO/C (1025) in MEEON, methylamino)carbonylpmethylene is hydrogenated at a temperature of 22°C for 5 hours (2.7 atm). The mixture is filtered. to obtain a white dry residue M4-(4-amino-3,4-dihydro-2H-s (5950368) 1-benzopyran-b-yl)-5-fluoro-M2-|3-(M-methylamino)carbonylmethyl enoxyphenyl|-2,4-pyrimidinediamine. "H NMR (MO): HI 9.60 (5, 1H), 9.46 (5, 1H), 8.73 (65, ZN), 800-810 p » (t, ZNU, 7.47 (5 ,1), 7.42 (t, 18), 7.294, 1H,1-7.2 5), 711 (1.2 7.2 Hz), 6.82 (y, i 1H,77.0 Gy) , 6.46 (t, IN), 4.23-4.46 (t, ZN), 4.31 (5, ZN), 2.63 (4, ZN, 1 2 4.8 Hz), 2, 09-2.29 (t, NU; LC/MS: purity: 97.695; MS (mass/charge: 438.98 (MH). 7.3.1181 M4-(3-methylcarbonylphenyl)-5-fluoro-M2- | B as a result of the reaction of a mixture of equimolar particles of 2-chloro-M4-(3-methylcarbonylphenyl)-5-

3-(M-methylamino)carbonylmethylene fluoro-4-aminopyridine and 3-(M-methylamino)carbonylmethyleneoxyaniline in MeOH in a tube

Go! oxyphenyl|-2,4-pyrimidinediamine of high pressure, at 110°C for 24 hours or in EN with microwave (8950371) heating to 175°C for 10-20 min. with subsequent water treatment, white dry residue M4-(3 -methylcarbonylphenyl)-5-fluoro-M2-13-(M-ko methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine. IN NMR (0M50): 7 16 -y 7 42) ko 60 b5

(5, 1H), 9.82 (5, 11), 8.24 (0, 1H, 7- 2.4 Gy), 8.15 (5, 1), 7.91-8.07 (t, 2NU, 7.70 (9, IN, 3- 70 gHz) 79 (I1H, 1-7.2 g Щ), 7.08-7.21 (t, ЗН), 6.564, 1Н, 2 -7.2 Gy ), 4.30 (5, ZN), 2.62 (4, ZN, 1-2 4.8 Hz), 2.48 (5, ZN); LC/MS: purity: 93.86; MS (mass charge: 410.50 (МН). 7.3.1142 M4-(3-phenylcarbonylpheny)-5-fluoro-M2- | As a result of the reaction of a mixture of equimolar particles of 2-chloro-M4-(3-phenylcarbonylphenyl)-3- ( 3-(M-methylamino)carbonylmethylene fluoro-4-aminopyridine and 3-(M-methylamino)carbonylmethyleneoxyaniline in MeOH in a high-pressure oxyphenyl|-2,4-pyrimidinediamine tube at 1107C for 24 hours or in EN at microwave (K950372) heating to 17572 for 10-20 Hz with a water-based treatment gives a white dry residue of М4-(3-phenylcarbonylphenyl)-5-feore-М2-|3-(М-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidineliamine. /MS; purity: 86095;

MS (mass/charge: 472.50 (МН). 7.3.1143 M4-(3-methylcarbonyloxyphenyl)-5- As a result of the reaction of the mixture MA-(3-methylcarbonylphenyl)-5-fluoro-M2-13-(M- fluoro -m2-|3-(M-methylamino)carbonylmethyleneoxyphenyl)-2,4-plirimidineliamine and hydroxylamine (20 methylamino)carbonylmethyleneoxyphenyl|- | equivalents) in pyridine at 227 for 16 hours with subsequent water treatment 2,4-pyrimidinediamine (K950373) we get a white dry residue of M4-(3-methylcarbonyloxyphenyl)-5-fluoro-M2-(3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine. "NN NMR (OM50): CI 2 (8, IN) 10 ,11 (5, 1H), 9.85 (5, 1H), 6.54-8.23 (t, 9H), 4.32 (8, 29), 2.63 (d, 1: 7.0 Hn, ZN), 2.47 (5, ZN); LC/MS: purity: 92.495; MS (mass/charge: 425.28 (MH). 7.311144 Ma-(3-phenylcarbonyloxyphenyl)-5- As a result of the reaction of the mixture MaA-(3-phenylcarbonylphenyl)-5-fluoro-ich2-134(M. fluoro-M2-|3-(M-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and hydroxylamine (20 methylamino)carbonylmethyleneoxyphenyl- | equivalents) in pyridine at 22"C draft after 16 hours with subsequent aqueous treatment of 2,4-pyrimidinediamine (K950374) we obtain a white dry residue of Ma-(3-phenylcarbonyloxyphenyl)-5-fluoro-M2-(3-(M-methylamino)carbonylmethyleneoxyphenyl)-2,4-lyrimidinediamine. "N.NMR (DM50); 0 11.63 (8, 1NU, 10.30 (5, IN), 9.85 (5, 1Н), 6.44-8.43 (t, 14Н), 4.42 ( 5, 2H), 2.63 (4, 1--7.0 Gy, ZM);

LC/MS: purity: 92.45; MS (mass/charge: 487.31 (MN). 7.3.1145 M2, Ma-bis(3-methylcarbonylphenyl)-5- As a result of the reaction of a mixture of 2,4-dichloro-5-fluoropyridine and three equivalents of 3- fluoro-2 ,4-pyrimidinediamine (950376) of acetophenone in MeOH in a high-pressure tube, at 10°C for 24 hours or in EUN with microwave heating to 1757 for 10-20 min., followed by water treatment, we obtain a white dry residue of M2,M4-bi( 3-methylcarbonylphenyl)-5-fluoro-2,-pyrimidinediamine. LC/MS: purity: 93.19; MS (mass/charge: 365.19 (MH). 7.3.1146 M2,M4-bis(3-phenylcarbonylphenyl) -5- As a result of the reaction of a mixture of 2,4-dichloro-5-fluoropyridine: three equivalents of 3-fluoro-2,4-pyrimidinediamine (K950377) benzophenone with MeOH in a high-pressure tube, at 1102C for 24 hours or in EN under microwave heating to 175"C for 10-20 min. with a water-based treatment, we get a white dry residue of M2,M4-bis(3-phenylcarbonylphenia)-5-fluoro-2,4-pyrimilindiamine. LC/MS: purity: 95.795; MS ( mass/charge. 489.29 (MN). ch 7.3.1147 M2/M4-bis(2,3-di hydro-4-benzipyranone- A solution of M2,M4-bis(4-methoxycarbonylethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine in b-yl)-5-fluoro-2,4-pyrimidinediamine TUN (trifluoromethanesulfonic acid) is heated to 100 "C for 2 hours. Aqueous Ge) (8950378) treatment followed by flash chromatography on silica gel gives the opportunity to obtain a white dry substance M2.ich4-bis(2,3-dihydro-4-benzipyranon-b-yl)-5-fluoro-2,4-pyrimidinediamine .

IN NMR (0M50): 2 9.36 (5, IN), 9.14 (5, 18), 8.06 (8, 1H, 1-2.4 Hz), 7.72-7.99 ( tt, ZNO), 6.97 (4.1-7.2 gy, 18), 6.87(4.12: 7.2 Hz, TE, 4.42-4.52 (iz, 4H)), 2.70-2.78 (t, 4H); LC/MS: purity: 94.39; MS (mass/charge: 484.50 (MN). "c 7.3.1148 M2,M4-bis(3-methylcarbonyloxyphenyl)- | As a result of the reaction of a mixture of M2,M4-bis(3-methylcarbonylphenyl)-5-fluoro-2 ,4-5-fluoro-2,4-pyrimidinedigmine (K950379) of pyrimidinediamine and hydroxylamine (29 equivalents) in pyriline at 22С for 16 hours with subsequent water treatment gives M2,M4-bis(3-methylcarbonyloxyphenyl)-b» 5-fluoro -2.4-pyrimidinediamine in the form of a white dry residue. "H NMR (0M503: HI 1121 (5.18), 0.11 (5, NN), 9.85 (5, 1H), 6.54-8.23 ( t, 9H), 4.32 (5, 2H), 2.63 (d, 3 7.0 Hz, ZN), che 2.47 (v, ZA); LC/MS: purity: 92.170; MS (mass /charge: 393.06 (M-H). 7.3.1149 M2,M4-bis(z-pheniacarbonyloxyphenyl)- | As a result of the reaction of the mixture M2,MaA-bis(3-phenylcarbonylphenyl)-5-fluoro-2,4- sem 5-fluoro-2,4-pyrmidinediamine (KU50380) of pyrimidinediamine and hydroxylamine (20 equivalents) in pyridine at 227C for 16 hours with subsequent water treatment gives the poor dry residue M2iM4-b12(3-s phenylcarbonyloxymphenyl)-5-fluoro-2 ,4-niyrimidinediamine LC/MS: purity a: 93.39; MS (mass/charge) in: 486.05 (M-N). 7.3.1159 M2,M4-bis(2,3-dihydro-4-oxim- As a result of the reaction of the mixture M2,M4-bis(2,3-dihydro-4-benzipyranon-6b-yl)-5-fluoro-2, of 4-benzipyran-b-yl.5-fluoro-2,4-pyrimidinediamine and hydroxylamine (29 equivalents) in pyridine at 222C for 16 hours with subsequent water treatment we obtain M2,M4-bis(2,3-dihydro -4-oxim-benzipliran-b-yl)-5-fluoro-2,4-pyrimidinediamine in the form of a white dry residue. LC/MS: purity: 98195; MS (mass/charge: 449.03 (MAN. 7.3. 1151 Ma-(4-acetyloxy-3,4-dihydro-2H-1- Solution M4A-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-b-yl)-5-fluoro-M2-|3 -(M- - s benzopyran-6-yl)-5-fluoro-M2-I|3-4(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinedismine in pyriline is treated with methylamino)carbonyl with acetic anhydride at a temperature of 22"C for 16 hours. After aqueous treatment with methyleneoxyphenyl|-2,4-pyrimidindiamine| a white dry residue MA-(4-acetyloxy-3,4-dihydro-2H-1-benzopyran-b-yl)-5- and t (K950382) is formed ) fluoro-m2-(3-(M-methylamino)carbonylmethylene oxyphene l|-2,4-pyrimidinediamine. "H NMR. (pM5OX 10.43 (65, 18), 9.62 (B5, 1), 8.03 (8, IN, 72 2.4 Gy), 7.10-7.83 (t, 7 ), 6.83 (y, 1H, 1-7.4 Hz), 6.524, EN, I 7.2 GR), 5.01 (t, IN), 4.75 (5, 2H), 4.03 -4.32 (t, 2H), 2.62 (5,

ZN), 2.23 (5, ZN), 1.93-2.13 (t, 2H); LC/MS: purity: 92.195; MS (mass/charge: 393.06 (M-

WELL. (ee) 7.311572 M4-(4-azido-3,4"dihydro-2H-1- Solution M4-(4-hydroxy-3,4-dihydro-2H-1-Bbenzopyran-b-yl)-5-fluoro- M2-134(M-benzopyran-6-yl)-5-fluoro-M2-|3-(M- methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in dry tetrahydrofuran

KkZz methylamino)carbonyl is treated with 2 equivalents of DFFA (diphenylphosphorylazide) and DBUS1,8- -y 7 42) ko 60 b5 methyleneoxyphenyl-2,4-pyrimidinediamine | diazabicyclo| 5.4.01undec)-7-sn). The mixture is stirred for 3 hours at 22", (K950383) evaporated to dryness and purified by flap chromatography on silica gel to give a white dry residue M4-(4-azido-3,4-dihydro-2H-1-benzopyran-6-yl) )-5-fluoro-

M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, "H NMR (OHM5O): 6 10.09 (bb, 1), 9.83 (B5, 1H), 8.18 (4, EN, 2 24 Hz), 7.97 (t, EN, 7.11-7.61 (t, 68), 6.82, 1H, 3 -7.8 Gy), 6.62 (4, 1H, 3 - 7.2 Hz), 4.78 (5, 2), 4.03-4.33 (t, ZY), 2.62 (5,

C), 1.93-2.13 (t, 2NU; LC/MS: purity: 97.995; MS (mass/charge)y: 463.07 (MH). 7.311153 M4-(4-benzipyran-6-yl) -5-fluoro-M2-(3- Solution IM4-(4-tihydroxy-3,4-dihydro-2H-1-benzopyran-b-yl)-5-fluoro-M2-13-(M-(M methylamino) carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in tetrahydrofuran methylamino)carbonylmethyleneoxyphenyl)- | is treated with boron trifluoride etherate at 807C for 8 hours. After aqueous 2,4-pyrimidinediamine (8950385) treatment, a white dry residue M4-(4-benzipyran-b- yl)-5-fluoro-M2-134(M-methylamino)carbonylmethyleneoxyphenylI|-2,4-pyrimidineliamine." NMR (0M5O0: 5 9.18 (5, 18), 9.14 (5, 1H), 8.03 (4.4 24 Hz, 1), 7.93 (bv5, 1H), 5.86-7.48 (t, 9H) 4.73-4.74 (n 28), 4.33 ( 5, NI), 2.62. (5, ZN); LC/MS: purity: 96.595; MS (mass/charge: 420.07 (MAN). 7.341154 M44(3-hydroxymethylene-4-methoxyphenyl)- ! B as a result of the reaction of a mixture of squimolar particles of 2-chloro-M4-(3-hydroxymethylene-4-5-fluoro-M2-13-(M-methoxyphenyl)-5-fluoro-4-aminopyridine and 3-(M-methylamino)carbonylmethylene oxaniline in methylamino)carbonylmethyleneoxyphenyl MeOH in a high-pressure tube, at 1107C for 24 hours or in OH at 2.4 pyrimidinediamine (K950386) microwave heating lo 17522 for 10-20 min. followed by water treatment, we obtain a white dry residue of M4-(3-hydroxymethylene-4-methoxyphenyl)-5-fluoro-M2-(3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, LC/MS: purity: 89, 29;

MS (mass/charge): 410.5 (MN). 7.3.1155 M4-(3-amino-4-ethoxyphenyl)-5-fluoro-M2- | As a result of the reaction of mixtures of 2-chloro-M4-(3-amino-4-ethoxyphenyl)-5-fluoro-4-aminopyridine and C

3-(M-methylamino)carbonylmethylene equivalents of 3-(M-methylamino)carbonylmethyleneoxyaniline in MeOH in a high-pressure oxyphenyl)-2,4-pyrimidinediamine tube chamber, at 1197 for 24 hours or in EYN under microwave heating to 1757 (K950388) during 10-20 min. with subsequent water treatment, a white dry residue of M4-(3-amino-4-ztoxyphenyl)-5-fluoro-M2-13-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained. LC/LMS: purity: 95.19; MS (mass/charge: 427.18 (MH). 7.311156 14(4-ethoxy-3-hydroxysulfonylphenyl)- | Solution M4-(4-hydroxy-3,4-digylro-2H-1-benzopyran-b-yl) -5-fluoro- M2-(34(M-5"fluoro-M2-13-(M" methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in NODe (acetic acid) methylamino)carbonylmethylene is treated with sodium nitrate, then concentrated brine is added acid and oxyphenyl-2,4-pyrimidinediamine copper dichloride. The sums are stirred for 2 hours at 22"C for 8 hours and (K950389) is purified by aqueous treatment followed by column chromatography on silica gel to obtain M4-(4-stoxy-3-hydroxysulfonylphenyl) -5-fluoro-M2-(34(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine. LC/MS: purity: 82.39;

MS (mass/charge: 474.09 (MAN. se 7.3.1157 M, Ma-bis(3-methoxycarbonyl-4- As a result of the reaction of a mixture of 2,4-dichloro-3-fluoropyridine and three equivalents of 3- He)trifluoromethoxyphenyl) -5-fluoro-2,4- methoxycarbonyl-4-trifluoromethoxyaniline in MeOH in a high-pressure tube, with pyrimidinediamine (2950391) at a temperature of 1107 for 10-20 min. methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. H NMR (0M50): δ 9.96 (5, 18), 9.82 (5, 1), 8.16-8.26 (t, 4), 7.91 (aa, 1H,1-3.0, 7.2 Sy), 7.42 (4, 1H, 17.2 Hz), 7.31 (4, 1H, 127, 2 Hz), 3.77 (5, ZNU, 3.75 (5, ZN);

LC/MS: purity: 93.095; MS (mass/charge: 565.37 (MIN). (se) 7.3.1158 m4-(3-methoxycarbonyl-4- As a result of the reaction of the sum of equimolar parts of 2-chloro-M4-(3-methoxycarboyl-4. trifluoromethoxyphenyl)- 5-fluoro-M2-I3-(M- | trifluoromethoxyphenyl)-5-fluoro-4-aminopyridine and 3-0M-(2) methylamino)carbonylmethyleneoxyphenyl)|- | methylamino)carbonylmethyleneoxyaniline in MEON in a high-pressure tube, when heating 2,4-pyrmidinediamine (B.950392) to 1107C for 24 hours or in ION with microwave heating to 1757C for 10-12 minutes. with subsequent treatment, we obtain a white dry residue of M4-(3-methoxycarbonyl-4-trifluoromethoxyphenyl)-5-fluoro-M2-Y3-4(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine. LC/MS: purity: 95.895; with.

MS (mass/charge)y; 10.41 (MN). 7.311159 4-(4-acetylamino-3,4-dihydro-2H-1- Solution Ma-(4-hydroxy-3,4-dihydro-2H-1-benzopyran-b-yl)-5-fluoro-M2-13 -(M- (he) benzopyran-b-yl)-5-fluoro-M2-13-(14-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in dry MeSM, the methylamino)carbonyl is treated with concentrated sulfuric acid. The mixture is stirred for three hours at 22"C, methyleneoxyphenyl|-2,4-pyrimidinediamine| is evaporated to dryness and purified by means of flash chromatography on silica gel to (Kk950393) obtain a white dry residue Ma-(y-epiethylamino-3,4-dihydro -?H-1-benzopyran-b-yl)-5-fluoro-112-13-0M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine. "NN NMR" (0M50): 6 10.46 (L5, IN ), 9.52 (b5, 1H), 7.98 (4, IN, 1-24 Hz), 7.12-7.73 (t, 7H), 6.66 (y, 1H, 1-7.2 g ), 6.490, 1H, 2 7.2 g), 4.75 (z, 2H), 4.03-4.32 (t, 2H)), 3.80 (t, 1). 2.64 (8,

ЗН), 2.143 (5, ЗН)), 1.90-2.11 (t, 2Н); LC/MS: purity: 92.195; MS (mass charge): 393.06 (MAH). - with LC/MS: purity: 96.25; MS (mass/charge: 479.13 (MAN). 7.341160 Hydrochloride M4-(4-amino-3,4-dihydro yl)-5-fluoro-M2-(3-0h-p z» 2H-1-benzopyran-b-yl)-5-fluoro-M2-|3-(M- | methylamino)carbonylmethyleneoxyphenyl|-2,4- Pyrimidinedismine in MEOV is treated with one p methylamino)carbonylmethylene equivalent of 1 M aqueous solution of NSI. The clear solution is evaporated to dryness and oxyphenyl|-2,4-pyrimidinediamine is washed with anhydrous acetone to obtain the hydrochloride (K950399) M4-(4-amino-3, 4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-M2-/3-0M-methylamino)carbonylmethyleneoxyphenylI-2.4-pyrimidinediamine in the form of a white dry note. LC/MS: purity: 98.25; MS (mass/charge: 438.98. (mA so 734161 Salt of succinic acid Ma-(4-amino-3,4- | Solution M4-4-amino-3,4-dihydro-2H- I-benzopyran-b- yl)-5-fluoro-M2-|3-0M- dihydro-2H-!-benzopyran-b-yl)-5-fluoro»methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in MEON is treated with one co M2-I3- (M-methylamino)carbonylmethylene equivalent of succinic acid. The transparent solution is evaporated to dryness, crystallized from 7 42) with 60 b5 of oxyphenyl|-2,4-pyrimylindiamine, the obtained dry powder from dry acetone to obtain a white dry residue of the salt (8950400) of succinic acid IM4-(4-amino-3,4- dihydro-2H-1-benzopyran-b-yl)-5-fluoro-M2-(3-(h-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine. LC/MS: purity: 98.15;

MS (mass charge. 438.98 (МН). 7.3.1162 Maleic acid salt M4-(4-amino- Solution M4-(4-amino-3,4-dihydro-2H-1-benzopyran-b-yl)-5 -fluoro-M2-13-0h- 3,a-dihydro-2H-|-benzopyran-b-yl)-5-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine in MEON is treated with one fluoro-M2-I340M- equivalent of maleic acid . The clear solution is evaporated to dryness, crystallized from methylamino)carbonylmethylene, the obtained dry residue from dry acetone to obtain the white dry residue of the oxyphenyl|-2,4-pyrimidinediamine salt of maleic acid MA-(4-amino-3,4-dihydro-2H-1-benzopyran- b-yl)-5-fluoro-M2-II3-(M-(K950401) methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidineliamine. RH/MIS; purity: 97.99;

MS (mass charge. 438.98 (МН). 7.3.1163 Fumaric acid salt M4-(4-amino- Solution M4-(4-amino-3,4-dihydro-7H. 1-benzopyran-b-yl)-5-fluoro -M2-I34(M- 3.4-dihydro-2H. | -benzoliran-b-yl)-5- methylamino)arbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in MeOH is treated with one fluoro-M2-13-(M- equivalent of fumaric acid . 6-yl)-5-fluoro-M2-13-(M-(Кк950402) methylamino)carbonylmethyleneoxyphenyl-2,4-tyrimidinediamine. LC/LMS: purity: 97995;

MC (mass charge): 438.98 (MN). 7.311164 Salt of citric acid M4-(4-Amino-Solution M4-(4-amino-3,4-dihydro-2H-1-benzopyran-6-yl)-5-fluoro-M2-(34(M- 3,4 -dihydro-2H-1-benzopyran-b-yl)-5-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine in MeOH is treated with one fluoro-Mm2-134(M-equivalent of citric acid. The clear solution is evaporated to dryness, methylamino)carbonylmethylene crystallizes the obtained dry residue from dry acetone to obtain a white dry residue of the oxyphenyl)|-2,4-pyrimidinediamine salt of citric acid M4A-(4-amino-3,4-dihydro-2H- and -benzopyran-b-1l)-5-fluoro -M2-E3-40M- (K950403) methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine. LC/MS: purity: 97.99;

MC (mass/charge): 438.98 (MN). 7.3.1165 NMO salt; M4-(4-Amino-3,4-dihydro-2H» | Solution Ma-(4-amino-3,4-dihydro-2H. 1-benzopyran-b-yl)-5-fluoro-M2-Y3-( M» 1-benzopyran-6-yl)-5-fluoro-M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine in MEOH is treated with one methylamino)carbsnylmethylene equivalent | M aqueous solution of НМОС», the clear solution is evaporated to dryness, the obtained dry residue of oxyphenyl|-2.4-pyrimidinediamine is crystallized from dry acetone to obtain a white dry (5950404) residue of the salt of nitric acid M4-(4-amino-3,4-dihydro-2H). - 1-benzopyran-6-yl)-5-fucor-M2- and 3-(M-methylamino)carbonylethyleneoxyphenyl|-2,4-pyrimidinediamine.. LC/MS; purity: 98.295; MS (mass/charge: 438.98 (Mn. 74 Synthesis of prodrugs) Typical prodrugs according to the structural formula (1I) were synthesized according to the following description. 4- Mixture of M2,M4-bis(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine, acetyl chloride (4 Ge) ethylenedioxyphenyl)-5-fluoro-2,4- equivalents), pyridine (4 equivalents ) in SNSI" is mixed with pyrimidinediamine (KU26233) at room temperature for 48 hours. After aqueous treatment, the precipitate is subjected to chromatography on silica gel to obtain M-2(4)-acetyl-M2,m4-bis(3,4-ethylenedioxyphenyl)-5- fluoro-2,4-pyrimidinediamine. "H NMR (SOCI"): 5 8.23 (y, IN, 1: 5.4 Gu, 7.03 (F, NN, 1-2.4 Gy), 7, 90-7.80 (t, ZMI), 6.76 (ta, 28), 4.28 (5, 4H)), 2.10 (in, ZNU; "E NMR (SOS); -42125; РХ/ MS: retention time: 27.94 min.; purity: 9995; MS (mass/charge: 439 (MH). (Che) z0 742 M2MA-bis(3-M-acetylaminophenyl)-5- M2,M4-bis( 3-aminophenyl)-5"fluoro-2,4-pyrimidinediamine, dimethylaminopyridine (DMAP) and

Fthor-M2, Ma-pyrimidinediacetylamine acetic anhydride is heated under reflux in pyridine for 1 hour. Ge") (K950244) The mixture is cooled to room temperature, evaporated and the precipitate is subjected to column chromatography on silica gel (SNCI:acetone, 2:1) to obtain M2,M4-bis(3-M-h: acetylamicophenyl)-5-fluoro- M2,M4-pyrimidinedisacetylamine. PH/MS: retention time: 17.03 min.; purity: 87.095; MS (mass/charge): 478.89 (MN). 7.4.3 m44(3-M,M-diacetylaminophenyl)-M2-(3- | M2,Ma-bis(3-aminophenyl)-5-fluoro-2,4-pyrzmidindismine, dimethylaminopyridine (DMAP) and

M-acetylaminophenyl)-5-fluoro-M2,M4-acetic anhydride is heated under reflux in pyridine for 1 hour. 3 pyrimidinediacetylamine (K950245) The mixture is cooled to room temperature, evaporated and the precipitate is subjected to column (co) chromatography on silica gel (SNCI:acetone, 2:1) to obtain М4-(3-М,М- diacetylaminophenyl)-М2-(3- M-acetylaminophenyl)-3-fluoro-M2, M-pyrimidinediacetylamine.

PH/MS: retention time: 19.27 min.; purity: 92.6; MS (mass/charge: 521.01 (MN). 744 M4-(3-M-vacetylaminophenia)-M2-(3-M,M- | M2,M4-bis(3-aminophenyl)-5-fluoro-2 ,4-pyrimidinediamine, dimethylaminopyridine (DMAP) and diacetylaminophenyl)-5-fluoro-M2,M4-acetic anhydride are heated under reflux in pyridine for | hour. "pyrimidinediacetylamine (K950246) The mixture is cooled to room temperature, evaporated and the precipitate is subjected to column chromatography on silica gel (SIS:acetone, 2:1) to obtain M4-Y3-M- acetylaminophenyl|-Mm2-(3-M,M-diacetylaminophenyl)5-fluoro-m2,M4-s pyrimidinediacetylamine. LC/MS: duration retention: 18.89 min.; purity: 83.090; MS (mass-charge): 520.97 (MAH). and - 745 M2,m4-bis(3-M.M-diacetylaminophenyl)-ma ma-Bis(3z -aminophenyl)-5-fluoro-2,4-pyrimidinediamine, dimethylaminopyridine (DMA) and 5-fluoro-M2,M4-pyrimidinediacetylamine acetic anhydride is heated under reflux in pyridine for 1 hour. (8950247) Sums are warmed to room temperature, evaporated and subject the precipitate to column chromatography on silica ale (SNSI. acetone, 2:1) to obtain М2,М4-bis(3-М,М-diacetylaminophenyl)-5-fluoro-М2,М4-pyrimidinedianethylamine. LC/MS: duration

Go! retention: 21.51 min.; purity: 91.898; MS (mass and charge: 563.00 (MN). seni 00200111 ko 746 Z-chloro-4- Dry reactor with magnetic stirrer, irrigation condenser and hole for -th 42) 60 b5

(methoxycarbonidmethyleneoxy)nitrobenz | feed M2 is filled with commercially available 2-chloro-4-nitrophenol (3.48 g, 20 mmol),

GO CoSO; (3.03 g, 21.81 mmol) and dry apetone (100 ml) in an atmosphere of M,. Methyl bromoacetate (1.72 mL, 18.18 mmol) was added to this mixture and heated at reflux for 2 hours. After cooling, the reaction mixture was dissolved in ice water (1 liter), and the resulting solid residue was filtered, washed with water (2 x 50 ml), and dried to obtain 33-chloro-4-(methoxycarbonylmethyleneoxy)nitrobenzene. /"H NMR (SOCI,): 5 8.33 (4, 1H, 1-3 Co), 8.13 (for 1n, 1- 2.7 apa 9.3 Gy), 6.87 (y, IN , 15 9.3 Gy), 4.84 (5, 280), 3.83 (5, ZN); LC/MS: purity: 8775; M5 (m/z): 287 (M acetonitrile), 74 chloro-4- To a solution of 3-chloro-4-(methoxycarbonylmethyleneoxy)nitrobenzene (1.00 g) in MeOH (50 ml) (methoxycarbonylmethyleneoxy)aniline, add 0.050 g of 1095 РО/С, degas and hydrogenate in a balloon filled with hydrogen ( near 1 atmosphere) for 2 hours. The reaction mixture is filtered through a pad of silica gel, concentrated, and the resulting precipitate is sonicated at 710 in the presence of stylacetate and filtered. The resulting filtrate is concentrated and dried under high vacuum to give 3-chloro-4-(methoxycarbonylmethyleneoxy)aniline .

IN NMR (SOS): 8 6.79 (0, 1H, 3-9 Hz), 6.73 (8, 1H, 222.1 Hz), 6.50 (49, 1H, 3-- 2.7 av 9, 3

Hz), 4.69 (5, 2H), 3.80 (5, ZNU; LC/MS: purity: 8795; M5 (m/z): 216 (MN. 7.4.8 Z-chloro-44(2. A dry reactor with a magnetic stirrer, an irrigation condenser, an opening for the supply of hydroxyethyleneoxy)nitrobenzene 72 and a rubber membrane is filled with 3-chloro-4-(methoxycarbonylmethyleneoxy)nitrobenzene (1.23 g, 5 mmol) and CH»CI2 (50 ml) under an atmosphere of M The reaction mixture is cooled to -78 °C and diisobutyllithium aluminum hydride (1.0 M in toluene, 15 ml, 15 mmol) is added to it over 15 minutes.

The reaction mixture is stirred at a temperature of -78 "C for 2 hours and at room temperature for 1 hour, cooled by rapid absorption in a saturated solution of ferruginous salt, and stirred again for 2 hours. As a result of extraction with the help of SNISI, drying over anhydrous Ma "5O" and evaporation of the solvent, 3-chloro-4-(2-hydroxytylenoxy)nitrobenzoic acid. "NH NMR (SOCI"): 5 8.30 (8, 1H, "3 gy), 8.15 (40, 18, le 2.4 and 9 Hn), 7.02 (0, IN, 1-87 Go), 4.25 (ZN, 1-: 4.8 Hz), 4.07 (t, 2H)Y; LC/MS: purity: 9295. 749 3-chloro-4-(2-hydroxyetmleneoxyaniline) Analogously to the preparation of 3-chloro-4-(methoxycarbonylmethyleneoxy aniline, as a result of hydrogenation of 3-chloro-4(2-hydroxyethyleneoxy)nitrobenzene with a balloon filled with hydrogen , (near | atmosphere) in the presence of 1095 Rd/С as a catalyst, we obtain 3-chloro-4-(2-hydroxyethyleneoxy)aniline. LC/MIS: M (m/z): 187 (M) 74410 2-(M-methylaminocarbonyl )-5- A dry reactor with a magnetic stirrer, a rubber membrane and a nitrobenzofuran feed hole is filled with 2-carboxy-5-nitrobenzofuran (2.07 g, 10 mmol), M,M-dimethylformamide sem (DMF) (0.100 ml) and SNOSI » (50 ml) in an atmosphere of Mo. The reaction mixture is cooled to a temperature of 0 °C and oxozyl chloride (XOXI) (2.65 ml, 30 mmol) is gradually added over 10 minutes. The reaction mixture is stirred for 2 hours until room temperature and also until the formation of a clear solution, the mixture is concentrated and dried under high vacuum to obtain intermediate chloride. to a temperature of 0 "C and add SNOOC (50 mL), pyriline (2.96 mL, 30 mmol), and then methylamine hydrochloride (1.34 g, 20 mmol). After stirring at (Che) for 24 hours at room temperature, the solvent is removed under reduced pressure, and the precipitate is suspended in free (200 mL). The obtained solid phase is filtered, thoroughly washed with water and dried to obtain 2-(M-methylaminocarbonyl)-5-(2)nitrobenzofuran. "H NMR (SOSI;): 8 8.63 (d, IN, 1-2.4 Gy), 8.33 (49, 1H, 122.4 and 93

Thy), 7.60, 1, 1- 7.8 Hyd), 7.59 (5, NU, 3.07 (0, ZN, 1» 4.8 Hz); LC/MS: purity: 9895; MS 221 (MIK). 5 vu, sem 2,3-dihydro|benzofuran Ma»5O,4 (1.5 v) Hydrogenated in MEON (200 ml) under a pressure of 3.7 atm for 3 days,

The resulting solution is filtered through a sipikagel pad, and concentrated to obtain (-)-5-amino-(2-(M-methylaminocarbonyl)-2,3-diginro|benzofuran. "NN NMR (SOCI»5): 5 6.65 (yiv, 21), 6.53 (t, 1), 5.01 (44, 1H, 7- 6.0 and 6.6 Gy), 3.46 (8th, IN, 7- 9.9 and 0 ,2 Hz), 3.18 (dy, 1H,, 7 6.0 and 4.2 Gy), 2.75 (8, ЗН). 74.12 2-(M,M-limethylaminocarbonyl)-5- Analogously to the preparation of 2-( M-methylaminocarbonyl)-5-nitrobenzofuran, as a result of the nitrobenzofuran reaction of 2-carboxy-5-nitrobenzofuran and oxalyl chloride followed by the addition of dimethylamine hydrochloride, 2-(M,M-dimethylaminocarbonyl)-5-nitrobenzofuran is obtained. : 6 8.61 (9, IN, 1-24 Gy), 8.31 (aa, IN, 12 2.4 and 9.3 Hu), 7.63 (4, 1H, 7-93

Hz), 7.40 95, IN), 3.35 (5, ZN), 3.17 (in, ZNU; RH/MS: purity: 9755; MS (m/zu: 235 (MN. shsh s 7443 ( )-5-amino-H2-(MuM- Analogously to the preparation of (--)-5-amino-/2-(M-methylaminocarbovia)-2,3- dimethylaminocarbonyl)-2,3- dihydro|benzofuran, as a result of hydrogenation of 2 -(M.M-dimethylaminocarbonyl)-5-h dihydro|benzofuran of nitrobenzofuran we get (-K)-5-amino-(2-(M,M-dimethylaminocarbonyl)-2,3- p» dihydro|benzofuran, "Н АМ (М50-46): 6 6.44 (t, 2Н), 6.27 (49, МН, 1: 2.1 and 8.7 ГИ), 5.42 (49, 1, 275 6.5 and 7 .5 Hn), 4.54 (80, 12 5.4 Hz), 3.23 (t, 2H)), 2.83 (5, ZN), 2.82 (8, ZN);

LC/MS: purity: 7092; MS (m/z): 207 (MN). 74414 2-48, 25, 5K)-menthyloxycarbonyl)-5- Similar to the preparation of 2-(-methylaminocarbonyl)-5-nitrobenzofuran, as a result

Go! nitrobenzofuran reaction of 2-carboxy-5-nitrobenzofuran with oxalyl chloride and subsequent treatment with (1K, 25, 583-(-)-menthol gives 2-((1K, 25, 5K)-menthyloxycarbonyl)-5-nitrobenzofuran. NMR (SOSI" in: 5 8.63 (8, IN, 1-72.4 Gy), 8.35 (ai, 1-24 and 8.7 Hn), 7.69 (4.1H, 3:93 Hz ), ko 7.62 (5, 1), 5.004 IN, 1- 4.8 and 10.5 Gy), 2.14 (68, 1H, 27-9.3 Gy), 1.95 (t, 18 ), 1.76 (t, -y 7 42) ko 60 b5

21), 1.56 (t, ЗН), 11 (t, 2Н), 0.94 (4, ЗН), 0.93 (y, ЗН), 0.82 (y, ЗН, 2- 7.2 Hz); LC/MS: purity: 99.6799. 7.4415 З-Amino-Y2(K)-(IK, 25, 58)- Similar to the preparation of ()-5-amino-|2-(M-methylamino)carbonyl-2,3-methyloxycarbonyl-2,3-dihydrobenzofuran, in as a result of hydrogenation of 2-((1К, 25, 5К)-menthyloxycarbonyl)-5-dihydrobenzofuran of nitrobenzofuran, we obtain the diastereomeric sum of 5-amino-|2-01К, 25, 5К)-menthyloxycarbonyl-2,3-dihydrobenzofuran, from which -|Y20B3IV, 25, 583- Menthyloxycarbonyl-2,3-dihydroyibenzofuran is separated as a crystalline diastereoisomer using the solvent diffusion method "(СН лсв-n-hexanes) during crystallization. "H NMR (SOCI"): 5 6.77 (64 , (1H), 6.73 (65, 1H)), 6.68 (04, TA, 1: 2.4 and 8.7

Sy), 5.144, 1H, 2-69 and 7.5 Gy), 4.76 (46, 4.5 and 14.1 Gy), 3.49 (49, IN, 1: 9.9 and 10.5 Hz), 32549, 1, 3 7.2 and 7.8 Hz), 199 (64, 1H), 1.86 (dreti, IN, /-: 3.0 and 6.9 Gy), 1.70 ( t, 18), 1.66 (t, IN), 1.46 (pu, 7NU, 1.02 (t, 18), 0.90 (4, ZN, 7.2 Gy), 0.89 (y , ZN, 2: 6.6 Hz), 0.75 (4,

ZN, Re 6.9 Hz); MS (m/z): ЗИ8 (МН), 7170 "Solvent diffusion method: The organic molecule is dissolved in a minimal amount

SNSI, and the vessel is placed in a beaker containing an antisolvent (n-hexanes), closed with a lid to prevent loss of solvent, and left to equilibrate until crystallization occurs. The resulting crystals are separated by decanting the solvent. 17.4.16 3,5-dichloro-4-methoxyaniline To a solution of commercially available 3,5-dichloro-2-methoxynitrobenzene (1.09 g, 4.5 mmol) in

Meon (1090 ml) add 1099 ROS (0.100 g), carry out degassing and hydrogenation using a balloon filled with hydrogen (approximately 1 atmosphere), over 2 streams.

As a result of filtration through celite and concentration, we obtain 3,5-dichloro-4-methoxyaniline, which is separated as 3,5-dichloro-4-methoxyaniline hydrochloride by oxidation with an equivalent amount of HC (AM, dioxane). Alternatively, this transformation can be obtained by mixing 3,5-dichloro-4-methoxynitrobenzene (1.00 g, 4.5 mmol) with Ma;55O, (3.91 g, 22.5 mmol) and K»CO» (3.12 g, 22.5 mmol) in MeOH:H,O (50 mL, each) at room temperature for 24 h. As a result of extraction with ethylacetate followed by removal of the solvent, 3,5-dichloro-4-methoxyaniline is obtained.

VK/MS: purity: 8795; MS (m/z): 233 (Mk acetonitrile), 7417 4-chloro-3Z-methoxyaniline To a solution of commercially available 3,5-dichloro-4-methoxynitrobenzene (1.09 g, 4.5 mmol) in

MeOH (100 mL) is added with 1099 PaC (0.100 g), then degassed and hydrogenated using a hydrogen-filled balloon (approximately 1 atmosphere) for 2 hours. As a result of filtration through celite and concentration, we obtain 3,5-dichloro-4-methoxyaniline, which is separated as 3,5-dichloro-4-methoxyaniline hydrochloride by oxidation with an equivalent amount of HCl (4M, dioxane)). Alternatively, such a transformation can be obtained as a result of mixing 3,5-dichloro-4- what and. that of methoxynitrobenzene (1.00 g, 4.5 mmol) with Ma»5»O4 3.91 g, 22.5 mmol) and KSO» (3.12 g, (o) 22.5 mmol) in MEOH:H .O (50 ml, each) at room temperature for 24 hours

As a result of extraction with stylacet followed by removal of the solvent, 3,5-dichloro-4-methoxyaniline is obtained. LC/MS: purity: 875; MS (m/z); 233 (M-acetonitrile). 74.18 d-chloro-3,5-dimethylaniline To a suspension of commercially available 4-chloro-3,5-dimethylnitrobenzene (0.185 g, 1 mmol) in

Ammonium chloride (0.265 g, 5 (se) mmol) and ferric ferrite (0.280 g, 5 mmol) were added to H.O. (5 mL, each) at room temperature, stirred for 5 minutes at room temperature, and then for 10 minutes at 60 "C. After cooling to room temperature, the reaction mixture is filtered through Celite, washed with ethanol and the filtrate is concentrated. The resulting precipitate is dissolved in water, saturated with sodium chloride and extracted with ethyl acetate. The organic solvent is removed under reduced pressure to obtain the desired 4-chloro -3,5-dimethylaniline. "H NMR (SOCI): δ 6.34 (5, 2H), 3.42 (bv, 2H), 2.20 (5, NU; LC/MS: purity: 8295; MS: 156 (MH). Ha! 7.A.19 3,4,5-trimethylaniline Analogous to the hydrogenation of 3-(methoxycarbonylmethyleneoxy)aniline, hydrogenation of commercially available 3,4,5-trimethylnitrobenzene yields 3,4,5- (ee) trimethylaniline LC/MS: purity: 9195 MS (m/z): 136 (MN).

Synthesis of mono-BMAg products (synthesis of substances based on the reaction of aromatic nucleophilic substitution) 74.20 Ma-chloro-M4A43-chloro-4- Sumigi 2,4-dichloro-5-fluoropyrimidine (0.305 g, 1.8 mmol) and 3-chloro- 4-" methoxycarbonylmethyleneoxyphenyl)-5-(methoxycarbonylmethyleneoxy)aniline (0.332 g, 1.2 mmol) is stirred in MEeOH:H.O (4

Yagogo-d-pyrimidinamine ml, each) at room temperature for 24 hours. The reaction mixture is dissolved in water (200 ml), treated with ultrasound for several minutes, left at room temperature for 30 minutes in order to sublimate (distill) 2,4-dichloro-5-fluoropyrimidine, and the resulting solid phase is filtered to obtain M2-chloro -M44(3-h with» chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidinamine. IN YAM" (SOS): P i 8.07 (d, 1H, 3-3 Gi), 7.56 (0, 1H, 72 2.4), 7.53 (40, 18, 2-2, and 9.3 Si), 6.90 (t, 2H), 4.72 (8, 2H), 3.82 (5, ZN); RF/MS: purity: 8095; MS (m/z): 346 (MN). 7.4.21 M2-chloro-Ma-|33-chloro-4-(2- Analogously to the preparation of 142-chloro-IR4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-hydroxyethyleneoxy)phenyl|- 5-fluoro-4 - fluoro-4-pyrimidinamine, M2-chloro-M4-13-chloro-4-(2-hydroxyethyleneoxy)phenyl|-5-fluoro-4-

Go | pyrimidineamine pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4(2-tihydroxytylenoxy)aniline. LC/MS: purity: 8495; MS (m/z): 318 (Mn. ke 7.422 A mixture of 2,4-dichloro-z-fluoropyrimidine (0.305 g, 1.8 mmol) and 3-chloro-4-fluoro-4-pyrimidinamine (methoxycarbonylmethyleneoxy)aniline (0.332 g, 1.2 mmol) are washed in MEON:HO»O (4 - and 7 42) to 60 b5 ml, each) at room temperature for 24 hours. The reaction mixture is dissolved in water (209 ml), treated with ultrasound for several minutes, left at room temperature for 30 minutes in order to sublimate the remaining 2,4-dichloro-5-fluoropyrimidine, and the resulting solid phase is filtered to obtain M2-chloro-M4- 4(3-chloro-4-methoxycarbonylmethyleneoxyphenia)-5-fluoro-4-pyrimidinamine. "H NMR (SOS): 2 8.07 (9, H, 1-3 Gy), 7.66 (0, 1H, 1- 2.4 H in), 7.53 (49, 1Hb 1- 2, 1 and 953 Gy), 6.90 (t, 28), 4.72 (5, 29), 3.82 (in, ZNU; RH/MS: purity: 8095; MS (m/z): 346 (MN ). 7423 M2-chloro-M4-|3-chloro-442- Similar to the preparation of M2-chloro-M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenia)-5-hydroxyethyleneoxy)phenyl|-5-fluoro-4-fluoro-4 -pyrimidinamine, M2-chloro-M4-|3-chloro-4-(2-hydroxyethyleneoxyphenyl|-5-fluoro-4-pyrimidinamine pyrimidineamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-chloro- "( 2-hydroxyethyleneoxy)aniline. LC/MIS: purity: 8495; MS (m/z): 318 (MG). 7.4.24 2-chloro-M4-4-chloro-3-methoxyphenia)-5- Analogously to the preparation of M2- chloro-M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-70 fluoro-4-pyrimidinamine fluoro-4-pyrimidineamine, M2-chloro-M4-(3-chloro-4-(2-dihydroxyethyleneoxy)phenyl)- 5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4-lichloro-5-fluoropyrimidine and 3-chloro-

A(2-hydroxyethyleneoxy aniline. LC/MS: purity: 8495; MS (m/z): ZIZ (MN). 74.25 2-chloro-Ma4-(4-chloro-3-methoxyphenyl)-5- Analogous to the preparation of M2- chloro-M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-2-fluoro-4-pyrimidinamine fluoro-4-pyrimidinamine, 2-chloro-M4-(4-chloro-3-methoxyphenyl)-5-fluoro-4-aminopyrimidine obtained as a result of the reaction of 2.4-dichloro-5-fluoropyrimidine and 4-chloro-3-methoxyaniline,

LC/MS: purity: 8825; MS (m/z3; 288 (MN). 74.26 2-chloro-M4-(3,5-dichloro-4-methoxyphenyl)- | Similar to the preparation of M2-chloro-M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5 - 5-fluoro-4-pyrimidinamine fluoro-4-pyrimidinamine, 2-chloro-M4-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine are obtained as a result of the reaction of 2,4-dichloro-5 -fluoropyrimidine with 3,5-dichloro-4-methoxyaniline hydrochloride. NAMe (0M5O-α6): 5 10.15 (8, MUU, 8.38 (9, 1H, 15 3.4 Gm), 7.86 ( y, 2H, 1-2: 3.0 Hn); LC/MS: purity: 9495; MS (m/z): 321 (MH). 74.27 Ma-42-aminopyrid-6-yl)-2-chloro- 5-Fluoro-4- | A mixture of 2,6-diaminopyridine (0.109 g, 1 mmol) and 2,4-dichloro-5-fluoropyrimidine (0.167 g, 1 pyrimidinamine mmol) in MeOH (7 mL) was shaken in a sealed tube at at a temperature of 60 C for 48 hours. The precipitate is concentrated and then adsorbed on silica gel and subjected to chromatography (silica gel; СНоСИ; then 195 g2M МНУМеОН in СНИСИ") with the formation of M4-(2-aminopyrid-b-yl)-2-chloro-5 -fluoro-4-pyrimidinamine. "H NAM? (C15OB): 6 8.16 (6, 1H, 1 3.6 Hz), 7.46 (t, 2H), 6.32 (44, 1H, and: 3.9 and 5.1 Giu; LC/MS: frequency: 806; MS (m/z): 240 (M). 74.28 Ma-(2-(M acetylamino)pyrid-6-yl-2- A dry reactor with a magnetic stirrer, a rubber membrane and an opening for feeding M. chloro-5-fluoro-4-pyrimidinamine is filled with M4-(2-aminopyrid-b -yl)-2-chloro-5-fluoro-4-pyrimidinamine (0.120 g, 0.5 mmol) and CH.Cl. After cooling to 0 °C, pyridine (0.100 mL, 1.0 mmol) and se subsequently histyl chloride (0.042 mL, 0.6 mmol) and stirred at room temperature (He) for 2 hours. The reaction mixture was cooled by rapid absorption into water, filtered over SNIS", dried over anhydrous Ma;5O0,, and the solvent was evaporated to give M4- /2-(M-acetylamino)pyrid-b-1l)-2-chloro-5-fluoro-4-pyrimidinamine. LC/MS: purity: 8096; MS (m/z): 292 (MH). 74.29 2- chloro-5-fluoro-Ma-12-(M- To a suspension of М4-(2-aminopyrid-b-yl)-2-chloro-5-fluoro-4-pyrimidinamine (0.06 g, 0.25 mmol) methylaminocarbonyl )aminopyrid-b-yl1- In TT F (1 ml) at 0 "С add tristylamine (0.050 ml, 0.35 mmol), 4-M,M-(se) 2,4-pyrimidinamine dimethylaminopyridmn (0.5 mg ) and triphostene (0.037 g, 0.125 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour, cooled by rapid absorption into an aqueous solution of methylamine (4095, 2 ml), shaken for 5 minutes and dissolved in water. The aqueous solution is extracted with ethyl acetate, the solvent is evaporated, and the precipitate is subjected to chromatography (silica gel; SNOSI; then 2-595 062M or

МН IMеОН in СНоСИи,) with the formation of 2-chloro-5-Fluoro-m4-12-(M-methylaminocarbonyl)aminopyrid-b-yl|-2,4-pyrimylinamine. "H NMR (OM5O-86): 5 10.34 s (5, 1), 9.34 (5, 1H), 8.72 (t, 1H), 8.45 (d, 1H, 3-- 3 .6 Hz), 7.65 (18, 4-8.1 Hyd), 7.52 (4, 1H, 1-5 7.8 Hz), 6.89 (8, 1H, 3-85, Hy) , 2.77 (4, ZN, 1-3.3 Gy); LC/MS: purity: 8890; MS (m/z): 297 (Mn. (ee) (001 d) Mma4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2- | A hermetically closed tube is filled with 2-chloro-Ch4-(4-chloro-3-methoxyphenyl)-5-fluoro-4- 13-(h- pyrimylinamine (0.109 g, 0.38 mmol), 3-(M-(methylamino)carbonylmethyleneoxy |znilin methylamino)carbonylmethyleneoxyphenyl|- | (0.068 g, 0.38 mmol) and MeOH (2 ml), then heated at a temperature of 100 " C for 2,4-pyrimidinediamine (К927042) 24 hours. After cooling to room temperature, the sum is dissolved in water, acidified, and the resulting solid phase is filtered, dried and purified by column chromatography (silica gel, СНоСиз then M МНУМеОН to 2-595 in SNSI;), ) obtaining M4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-4(M- with methylamino)carboniamethyleneoxyphenyl-2,4-pyrimidinediami N. Alternatively, the obtained reaction is dissolved with ethyl acetate, the solid phase is separated using the centrifuge method and subjected to purification by the above method. Thus, most of the unreacted mono-5MAg product and secondary aniline pass into ethyl anethate, and the desired bis-XMAg product remains in the solid phase. "H YAM? (0M5O0-46): 5 9.89 (b, 1H), 9.66 (p5, 1H), 8.209, 1H, 15 4.8 Hz), 7.95 (Ba, 1NU, 7, 48 (t, 2NU, 7.33 (y, 1H, 75 9.3 Hz), 7.26 (B5, 1H), 7.17 (p 2H), 6.57 (Ba, 1H, 2: 7, 8 Gy), 4.34 (5, 2H), 3.72 (5, ZNI), 2.66 (5, ZN);

LC/MS: purity: 9796; MS (m/z): 432 (MN). so 7.4.31 M4-(3-chloro-4- Analogous to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-(M- methoxycarbonylmethyleneoxyphenyl)-5- methylamino)carbonylmethyleneoxyphenyl-2,4 -pyrimidinediamine, M44(3-chlor-4- -y 42) 60 b5 fluoro-M2-I3-49M- methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-13-01M- methylamino)carbonylmethyleneoxyphenyl- | methylamino)carbonylmethyleneoxyphenyl)-2,8-pyrimidinediamine is obtained as a result of the reaction of 2,4-pyrimidinediamine with М2-chloro-M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-4-pyrimidinamine and 3-/M-(methylamino)carbonylmethyleneoxy |znilina INT/MIS: purity: 8195;

MS (m/z)y: 490 (МН. 7.А32 MA-13-chloro-44(М- The hermetically closed tube is filled with М4-(3-chloro-4-methylamino)carbonylmethyleneoxyphenyl|- | methoxycarbonylmethyleneoxyphenyl)-5-fluorine -M2-13-(M-5-fluoro-M2-(340M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinelyamine (0.123 g, 0.25 mmol), methylamico)carbonylmethyleneoxyphenyl)» | methylamine hydrochloride (0.084 g, 1.25 mmol), diisopropylethylamine (0.217 ml, 1.25 2.A-pyrimidinediamine (2927043) mmol) and MeOH (4 ml) and heated at 100 "C for 24 hours. After cooling to room temperature temperature, the mixture is dissolved in water (50 mL), extracted with ethyl acetate (3 x 25 mL), and the organic solvent is evaporated. The resulting precipitate is purified by column chromatography (silica gel, SNCI, then 24 MNUMeOH 70 to 295 in СНоСИ"), obtaining M4- |3-chloro-4-(M-methylamino)carbonylmethyleneoxyphenyl|-3-fluoro-M2-(3-(M-methylamino)carbonylmethyleneoxyphenia|-2,4-pyrimidineliamine, "H NMR (OM5O-45): 5 9, 35 (5, TN), 9.24 (b5, NN). 8.09 (4, IN, 7- 3.6 Gy), 7.94 (Ba, 18), 7.87 (64, IN, 1-42 Hz) , 7.83 (6 18, 45 2.4 Hz), 7.72 (t, IN), 7.29 (t, 2H), 7.11 (5 IN, )- 8.4 Hz), 6, 99 (9, 1H, and: 8.7 Gy), 6.47 (44, 1H, I 1.8 and 10.5 Hz), 4.53 (8, 2H), 4.33 (8, 2H) ), 2.66 (d, ZN, 12 4.8

Hz), 2.63 (4, ZN, 7-4.8 Gu); LC/MS: purity: 9295; MS (m/z): 489 (MN). 7.4.33 T4-(3-chloro-4-(2- Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2- hydroxyethyleneoxy )phenyl|-5-fluoro-YM2- IZ-(M -methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-|3-chloro-4-(2- (3 hydroxystylenoxy)phenyl-5-fluoro-M2-I|3-(M-methylamino)carbonylmethyleneoxyphenyl|-2, 4-methylamino)carbonylmethyleneoxyphenyl|-|pyrimidinediamine is obtained as a result of the reaction of M2-chloro-M4-|3-chloro-4-(2- 2,4-pyrimidinediamine (2927047) tihydroxytyleneoxy)phenyl-5-fluoro-4-pyrimidinamine and 3 -HM- (methylamino)carbonylmethyleneoxy|aniline. "NN NMR (0M5O0-46): 6 9.31 (5, 1H)), 9.22 (5, 1H), 8.08 (d0, 1H, 1-3 .6 Hz), 7.94 (t, 114), 7.80 (4, 1H, 1 2.4 Gy), 7.68 (av, 1H, 7-24 and 8.7

Gi), 7.31 (65.18), 7.29 (8, 1H, 1-1.2 Hz), 7.10 (t, 2H), 6.46 (to, TN), 4.34 ( in, 28), 4.04 (1, 2Н,

And 5.4 Hz), 3.71 (2Н, 7-5, Hz), 2.62 (4, ЗН, 1 4.8 Hz); LC/MS: purity: 8995; MS (m/z)y: 862 (MN) 7.4.34 M443,5-dichloro-4-methoxyphenyl)-5-fluoro- | Similarly to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-m2413-(M- I3-(M-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine, M4-(3,5-dichloro- 4-methylamino)carbonylmethyleneoxyphenyl|- | methoxyphenyl)-3-fluoro-142-134M-methylamino)carbonylmethyleneoxyphenyl)-2,4- 2.A-pyrimidinediamine (1927057) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M44(3,5-dichloro-4-methoxyphenyl)- 5-fluoro-4-pyrimidinamine and 3-| M-(methylamino)carbonylmethyleneoxy |aniline. N YAM? (0М50-46): 5 9.80 (5, 1), 9.60 (б5, 1), 8.21 (4, МН, 1-- 3.6 Hyd), 7.98 (ва, 1) . M44(2-aminopyrid-6-yl)-5-fluoro-ich2-|3- Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-ich2- (M- (3-(M-methylamino )carbonylmethyleneoxyphenide)-2,4-pyrimidinediamine, M4-(2-aminopyride-b-methylamino)carbonylmethyleneoxyphenyl)- | )-5-fluoro-M2-(34(M-(methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine 2,4-pyrimidinediamine (8927080) is obtained as a result of the reaction of M4-(2-aminopyrid-b-yl)-2-chloro-5-fluoro-4-pyrimidinamine and 3-H-(methylamino)carbonylmethyleneoxy aniline. ): 5 7.96 (a, IN, 1- 3.0 (Che)

Gi), 7.58 (y, 1, 1 7.8 Hz), 7.40 (t, 2H), 7.17 (t, 2H), 6.60 (to, 1H), 6.27 (80, IN . -acetylamino)pyrid-b-yl|-5- Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenial)-5-fluoro-Mo» fluoro-m2-(3-(M-(3-09-methylamino)carbonylmethyleneoxyphene) li-2,4-pyrimidinediamine, M4-(2-0M-h-methylamino)carbonylmethyleneoxyphenyl|.|acetylamino)pyrid-6b-1l|-5-fluoro-M2-|34(M-methylamino)carbonylmethyleneoxyphenyl)-2, 4- 2,A-pyrimidinediamine (К927093) pyrimidinediamine is obtained as a result of the reaction of М4-(2-(M-acetylamino)pyrid-6-yl|-2-chloro-5-fluoro-4-pyrimidinamine and 3-(M-( methylamino)carbonylmethyleneoxy aniline

NMR (0M50-46): 6 10.22 (5, IN), 9.35 (5, 1H), 9.05 (5, 1H), 8.184, 1H, 7- 3.3 Hz), 7.96 (t,

INU, 7.75 (5, 7NU, 7.38 (B5, 1), 7.29 (4, IN, 2-84 Ha), 7.11 (y, 1H, 7- 8.4 Hn), 6 ,49 (Baa, IN, co

Te 8.4 gy), 4.37 (8, 2), 2.65 (y, 314), 2.18 (in, ZNU; RH/MS: purity: 8095; MS (m/z): 426 (m) 74.37 Mm4-(3-chloro-y-methoxyphenyl)-M2-(3,5- Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-Madichloro-4-hydroxyphenyl)-5-fluoro -2,4- И34СМ-methylamino)carbonylmethylevoxyphenyl)-2,4-pyrimidinediamine, М4А-(3-chloro-4- pyrmidinediamine (K927044) methoxyphenyl)-М2-(3,5-nichloro-4-hyloxyphenyl)-5- fluoro-2,4-pyrimicindiamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and 3,5-dichloro-4-hydroxyaniline. "H| NMR (0M50-46); 5 9.46 (z, 18), 9.34 (in, 1), 9.22 (in, 1H), 8.09 (4, 1H, 23.6 Gy ), 7.66 (t, 13), 7.63 (t, 2H), 7.10 (4, 1H, 1- 9.3 Hz), 3.82 (in, ZNU; RU/MS: - s purity: 10995; MS (m/3): 430 (МН. 7.4.38 М44(3-chloro-4-trifluoromethoxyphenyl)-М2- | Similar to the preparation of М4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro- M2- h z" (3,5-dichloro-4-hydroxyphenyl)-5-fluoro-2,4- pyrimidinediamine (2927046) trifluoromethoxyphenyl)-M2-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-trifluoromethoxyphenyl)- 5-fluoro-4-pyrimidinamine and 3,5-dichloro-4-hydroxyaniline. "H NMR (2M3O-46): 6 9.70 (5, 1), 9.54 (5, 1H), 9.35 ( 5, IN), 8.20 (a, 18, 4-3.6 Hz), 8.01 (0, IN, 1-3 ih), 7.85 (t, 133), 7.65 (5, 18). .39 M2-43,5-pichloro-4-hydroxyphenyl)-M4-(2,2- | Similar to the preparation of M4-(3-chloro-4-m ethoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-difluoro-3-oxo-4H-benzi I Foxazine-b- I3-0M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M2-(3,5-dichloro-4-kzyl )-5-fluoro-72,4-pyrkmidinediamine tihydroxyphenyl)-M4-(2,2-difluoro-3-oxo-4H-benz| And 4-oxazin-6-yl)-5-fluoro-2,4-th (k927048) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-difluoro-3-oxo-4H-)th (Ce) 42) ko 60 b5

(8927048) benzo(1,4-oxazin-b-yl)-5-fluoro-4-pyrimidinamine and 3,5-dichloro-4-hydroxyaniline. YAN NMR (rm50-ab6u: 6 11.96 (8, 1H), 9.58 (5, IN), 9.47 (5, 1H), 9.27 (5, 1H), 8.13 (4, 1H, 1-3.6 Hz), 7.65 (5, 28), 7.38 (t, 28), 7.25 (4, IN, 1-9 Hz); LC/MS: purity: 9296; MS (m/4): 472 (МН. 7.4.0 М2-(3,5-dichloro-d-hydroxyphenyl)-М4-(2,2- | Similar to the preparation of М4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl) -5-fluoro-M2-dimethyl-3-oxo-4H-benzi 1, oxazine-b- (3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(3,5-dichloro-4- yl)-5-fluoro-2,4-pyrimidinediamine hydroxyphenia)-m4-(2,2-dimethyl-3-oxo-4NH-benz (1 oxazin-b-yl)-5-fluoro-2,4- (8927051 ) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-dimethyl-3-oxo-4H-benzyl)-5-fluoro-4-pyrimidinamine and 3,5- dichloro-4-hydroxyaniline. "H NMR (0M50-46): 5 10.61 (5, 1H), 9.45 (5, IN), 9.34 (5, 1H), 9.18 (in, 1H ), 8.07 (66, 180), 7.66 (b, 2H), 7.23 (B, 1H, I 8.1 Gu, 7.12 (5, NNI), 6.88 (4, IN , I- 8.4 Gy), 1.39 (5, CH);

LC/MS: purity: 10095; MS (m/z3): 464 (MN). 70 74.41 MA-(3-chloro-4-methoxyphenyl)-M2-(3,5- Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyal)-5-fluoro-M2-dichloro-4-methoxyphenyl)-5- fluoro-2,4- (34(M-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine, M4-(3-chloro-4-pyrimidinediamine (K927054) methoxyphenyl)-M2-(3,5-dichloro-4-methoxyphenyl) )-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinamine and hydrochloride 3,5-dichloro-4- methoxyaniline. "H NMR (РМ5О0-96): b 9.46 (5, 1Н), 9.42 (5, 1), 8.12 (4, IN, 7-Z Hyk), 7.73 (5, 2Н) ), 7.65 (y, 1H, 1- 2.4 Hyd), 7.60 (09, 1H, 12.1 and 8.7 Hz), 7.124, IN, 1 8.7 Hn), 3.84 (5, ZN), 3.73 (5, ZN), LC/MS: purity: 9795; MS (m/z): 443 (Mn. 74.42 Mma-(3-chloro-4-trifluoromethoxyphenyl)-M2- | Similarly to the preparation of Ma-(3-chloro-4-methoxycarbonylmethyleneoxyphenia)-5-fluoro-M2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4- | (3-(M-methylamino)carbonylstyreneoxyphenyl |-2,4-pyrimidinediamine, M4-(3-chloro-4-pyrimidinediamine (2927055) trifluoromethoxyphenyl)-M2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result reaction of 2-chloro-M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinamine and 3,5-dichloro-4-methoxyaniline hydrochloride. "H NMR (YUMI5O-46); 5 9, 77 (5, 1H), 9.59 (5, 1), 8.23 (0, 1H, 1: 3.9 Hy), 8.00 (4, 1, 72 2.1 Hy), 7.84 (44, NN, re 2.7 and 9.0

Hz), 7.75 (4, 2H, 1-5 1.5 Gy), 7.50 (04, 1H, 3- 9.3 Hn), 3.74 (5, ZN); LC/MS: purity: 7990; MS (m/z): 499 (ME). 7.4.43 Mm443, 4 dichlorophenyl)-M2-(3,5-dichloro-4- Similar to the preparation of M4A-(3-chloro-4-methoxycarbonylmethyleneoxyphenia)-5-fluoro-M2- methoxyphenyl)-5-fluoro-2,4 - I3-(M-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine, M4-(3,4-pyrimidinediamine (927058) dichlorophenyl)-M2-4(3,5-dichloro-4-methoxyphenyl)-5-fluoro- 2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-diyuurphenyl)-5-fluoro-2,4-pyrimidinamine and 3,5-dichloro-d-methoxyaniline hydrochloride. LC/MS: purity: 9395; MS (m/z)y: 449 (MN). 7.4 44 7m2-(3,5-dichloro-4-methoxyphenyl)-M4-(2,2- | Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyal)-5-fluoro-M2- dimethynl-3-oxo- 4H-benzi I. Yaoxazin-b- I3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M2-(3,5-vichloro-4-c29yl)-5-fluoro-2,4-tyrimylindiamine methoxyphenyl )-M4-2,7-dimethyl-3-oxo-4H-benz 1,4 |oxazin-5-yl)-5-fluoro-2,4-He) (8927056) pyrimidinediamine is obtained as a result of the reaction of 2-chloro- M4-(2,2-nimethyl-3-oxo-4H-benz(II,NCoxazineb-yl)-5-fluoro-4-pyrimidicamine and 3,5-dichloro-4-methoxyaniline hydrochloride. LC/MS: purity: 9255 ; MS (m/z): 478 (MN). 7445 1h2-(3,5-dichloro-4-methoxyphenyl)-M4-(2,2- | Similar to the preparation of Ma4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)- 5-fluoro-M2-difluoro-Z-oxo-4H-benzi 1,4 oxazine-6b- 13-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrmidinediamine, M2-(3,5-dichloro-4- (Te il), 5-fluoro-2,4-pyrimidinedismin methoxyphenyl)-Ma4-(2,2-difluoro-3-oxo-4H-benzi 1,4 |oxazin-3-6-id)-5-fluoro-2, 4- (927061) pyrimidinediamine is obtained in as a result of the reaction of 2-chloro-MA-(2,2"difluoro-3-oxoYAN" benzyl 1.oxazin-6-ip)-5-fluoro-4-pyrimidinamine and 3,5-dichloro-4-He") methoxyaniline hydrochloride . "NMR (0M50-46): 5 11.95 (in, IN), 9.64 (5, IN), 9.50 (5, EN), 8.16 (4, IN, 1-2 3 .6 Gy), 7.74 (v, 2H), 7.38 (t, 2H), 7.26 (t, 1H), 3.71 (5, ZN); LC/MS: purity: 9295; MS che (mizu: 486 (МН). 7.44 2-4(3,5-dimethoxyphenia)-M4-(2,2- Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-Ha dimethyl -3-oxo-4H-benzi 1,oxazine-3-13-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(3,5-b-yl)y-5-fluoro-2,4 -pyrimidinediamine dimethoxyphenia)-M4-(2,2-dimethyl-3-oxo-4H-benz(1,oxazin-b-yl)-5-fluoro-2,4-

Zo (8927050) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-dimethyl-3-oxo-4H.ge)benz( and oxazin-3-6-yl)-5-fluoro-4-pyrimidinamine and 3,5-dimethoxyaniline. "H NMR (0M50-46): 5 10.53 (5, 1HO), 9.31 (z, IN), 8.99 (5, EN), 8.06 (0, IV, 7- 3.9 E), 7.26 (t, 2HO, 6.93 (5, 1H), 6.92 (5, 1H), 6.85 (4, 1H, 3-8.7 Gsh), 6.03 (01.7 : 2.4 Gy), 3.01 (5, 6H), 1.39 (5,

NN); LC/MS: purity: 9295; MO (m/z): 440 (MN). 7447 Ма4-(3,4-dichlorophenyl)-Мм2-(3,5- Similar to the preparation of М4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-М2- "dimethoxyphenia)-5-fluoro-2,4- 13-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3,4-pyrimidinediamine (927060) dichlorophenyl)-M2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine are obtained as a result of the reaction of 2-chloro-M4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidinamine and 3,5-dimethoxyniline. /H s NMR (pM5O-46): δ 9.60 (5, 1H), 9.26 (5, 1H), 8.16 (d, 1H, 2- 3.6 Gy), 8.08 (2 , 1H, 3- 3.0 g), 7.85 (t, IN), 7.51 (4, 1H, 7-9.0 Go), 6.89 0 ZA, 1-2, Hz), 6 .08 (b IN, 32 2.4 Gi), 3.64 (8, h z» NO); LC/MS: purity: 9696; MS (m/z)y: 409 (MN). " 7.4,48 Ма4(3-chloro-4-methoxyphenyl)-М2-(3,5- Similar to the preparation of М4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-2-dimethoxyphenyl)-5-fluoro-2 ,4- 13-(m-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3-chloro-4» pyrimidinediamine (K927056) methoxyphenyl)-M2-(3,5-dimethoxyphenyl)-5-fluoro-7 ,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and 3,5-so dimethoxyanilic. 9.31 (5, 18), 9.14 (5, 18), 8.08 4.18, 2- 3.3 Gy), 7.74 (t, 2H), 7.08 (4, 1H, 12 8.7 GP), 6.90 (9, 2H, 7- 21 P) 6.05 (6, 1, 3- 2.4 Gy), 3.84 (in,

ZN), 3.63 (5, 6); LC/MS: purity: 10095; MS (m/z); 405 (MN). ko -y (Se) 42) ko 60 b5

7449 ma-(3-chloro-4-trifluoromethoxyphenyl)-M2- | Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyyl)-5-fluoro-M2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-Y3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine . -4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidinamine and 3,5-dimethoxyaniline. "H NMR (0М50-46): 8 9.67 (5, IN), 9.28 (х, 18), 8.18 (4, 1Н, 22 36

Hz 8.090 1H.3- 1.2 Hn), 7.91 (49, IN, 3: 2.7 and 9.0 Hz), 7.45 (By, IN, 1- 9.0 Hn), 6, 89 (d, 2H, re 1.8 Hz), 6.08 (5, 18), 3.64 (5, 6H); LC/MS: purity: 97; MS (m/1): 459 (MN). 7.4.50 m4-(2-aminopyrid-6-yl)-M2-(3,5- Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxypheny)-5-fluoro-YH2- dimethoxyphenyl)-5-fluoro-2 ,4-Y3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, MA-|2-aminopyrid-b- pyrimidinediamine (927077) yl)-M2-(3,5-dimethoxyphenyl)-5-fluoro-2, 4-pyrimidinediamine is obtained as a result of the reaction

Ma-(2-aminopyrid-b-yl)-2-chloro-5-fluoro-4-pyrimidinamine and 3,5-dimethoxyaniline. "H NMR (SOS): 5 8.00 (05, 1H), 7.75 (Ba, 1NU, 7.45 (6 1H), 7.30 (b5, 1H), 7.25 (05, 1) , 7.05 (B5, INU 6.80 (68, 2), 6.20 (t, 2H), 4.35 (65, NI), 3.75 (5, 6); LC/MS: purity: 915; MS (m/z: 357 (MH. 74.51 M2-(3,5-dimethoxyphenyl)-5-fluoro-M4- Analogously to the preparation of IM4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5 "fluoro-Ma" ( indo-b-yl)-2,4-pyrimylindiaminium p3a(M-methylaminocarbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M2-(3,5- (8927089) dimethoxyphenyl)-5-fluoro-M4-(indole-b-yl) -2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-Ma-(indol-6-yl)-4-pyrimidinamine and 3,5-dimethoxyaniline. /H NMR. (SOS): 5 8.60 (05, EN), 8.43 (5.1), 7.90 (4, IN, 72 3.3 Gy), 7.56 (a, IN, 75 8.4 Gy), 7.22 (t , 2), 6.95 (Ba, 18), 6.88 (49, 1H, 1- 1.8 and 8.4 Hz), 6.82 (5, 1H), 6.81 (5, IN), 6 .52 (BE, IN), 6.25 p, IN, 32 1.8 Hz), 3.74 (5, 6H); LC/MS: purity: 975; MS (m/z): 380 (MH U 74.52 M44124(M-acetylamino)pyrid-6-epi-M2- Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M O- (3.5-dimethoxyphenyl)-5-fluoro-2,4- (3-0m-methylaminocarbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(2-0Mch- pyrimidinediamine (К927096) acetylamino)pyrid-6-yl|- M2-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinlyamine is obtained as a result of the reaction of 144-42-40 -epiethylamino)pyrid-b-yl)-2-chloro-5-fluoro-4-pyrimidinamine and 3,5-dimethoxyaniline. LC/MS: purity: 8205, MS (m/z): 399 (Mn. 74.53 1х2-4-3,5-dichlorophenyl)-M4-(2,2-dimethyl-3- | Similar to the preparation of M4-(3- chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-oxo-4H-benz|1,4)oxazin-b-yl)-5-fluoro- | I3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(3,5-2,4-pyrimidinediamine (K927064) dichlorophenyl)-Ma-(2,2-dimethyl-3-oxo-4H-benzi 1,4 |oxazin-b-yl)-5-fluoro-2,4-pyrimidinidiamine is obtained as a result of the reaction of 2-chloro-M44(2,2-dimethyl-3-oxo-4H-benz| and, Tsoxazin-6- yl)-5-fluoro-4-pyrimidinamine and 3,5-dichloroaniline. "H NMR (OM5O-46): 5 10.61 (5, 1H), 9.55 (5, 1H), 9.42 (8, 1H), 8.13 (0, IN, 7: 3.6 Hz), 7.74 (5, 1H), 7.73 (5, 1H), 7.21 (Vol. 1), 7.11 (5.1), 6.98 (5, 1), 6, 90 (9, 1H, 1-8.7 Hz), 1.38 (5, 6H); LC/MS: purity: 91955 MIS (m/z): 448 (MN). s 74.54 M44(2, 2-limethyl-3-oxo-4H- Analogously to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-benz|1,4)oxase n-6-yl)-5-fluoro-M2- 43- 13-(M-methylamino)carboniamethyleneoxyphenyl)-2,4-pyrimidinediamine, M4-(2,2-dimethyl-3-o methoxy-5-trifluoromethylphenyl)-2,4-oxo-4H-benz|1,4 |oxazin-6-yl)-5-fluoro-M2-(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine (K927065) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-dimethyl- 3-oxo-4H-benz 1,4)oxazin-b-yl)-5-fluoro-4-pyrimidinamine and 3-methoxy-5-trifluoromethylaniline. H

NMR (0M5O0-46u; 8 10.57 (8, IN), 9.41 (8, IN), 9.38 (5, 1H), 8.11 (4, IN, 3»: 3.6 Gy) , 7.65 (in,

IN, 7.59 (5.18), 7.30 (t, 18), 7.18 (5, 180), 6.85 (4, 1H, 25 8.7 Gy), 0.69 (5, 1) , 3.70 (5, ZN), "se 1.39 (5, 6H); LC/MS: purity: 9892; MS (m/3): 478 (MN). 7-4.55 142-(2,6-dimethoxypyrid-3-yl)-M44(2,2- Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethylecoxyphenyl)-5-fluoro-M2-b dimethyl-3-oxo- 4H-benz|1,4|oxazine-b-Y3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinethiamine, M2-(2,6-yl)-5-fluoro-2,4-pyrimidinediamine dimethoxypyrid- 3-yl)-m4-(2,2-dimethyl-3-oxo-4H-benz|1,Noxazin-b-yl)-5-fluoro-2,4- (8927068) pyrimidinediamine is obtained as a result of the reaction of 2-chloro -M4-(2,2-dimethyl-3-oxo-4H-che benzyl, doxazin-b-yl)-5-fluoro-4-pyrimidinamine and 3-amino-2,6-dimethoxypyridine. /N

LMR (OM50-y6); 5 10.56 (z, INU, 9.28 (5, 1H)), 7.87 (14, 2H), 7.67 (5, 1), 7.34 (in, 18), 7.16 se (44.1 H, 1-21 and 8.4 Gy), 6.79 (y, 1H, 72» 8.7 Gy), 6.26 (4, IN, 4- 8.4 Gyd), 3, 87 (5, ZNU), 3.82 (5,

ZM), 1.39 (5, 6H); LC/MS: purity: 9790; MS (m/z): 441 (MN). 7.4.56 M2-022,6-dimethylphenyl)-M4-(2,2-dimethyl- | Similar to the preparation of Im4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-Х2- со 3-oxo-4H-benz | and, oxazin-6-yl)-5- T3-(M-methylamino)carbovylmethyleneoxyphenyl/|-2,4-pyrimidinediamine, M2-(2,6-fluoro-2,4-pyrimidinediamine (K927069) dimethylphenyl)-M4 -(2,2-dimethyl-3-oxo-4H-benz| 1,4 |oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2 -dimethyl-3-oxo-4H, benzo[1,oxazin-6-yl)-5-fluoro-4-pyrimidinamine 3,5-dimethylaniline. NMR (M5o-av): 5 10.74 (5, IN), 10.40 (bx, 1H)), 10.10 (b5, 1H), 8.25 (Ba, iH), 7.24 944, 1Н, 7- 2.4 and 8.1 Hz), « 7.445, 1), 7.09 (в8, 2Н), 6.92 (0, 1Н, 2» 9.0 Hz), 6.68 (б5 , 1), 2.16 (5, 5H)), 1.40 (5, 58);

LC/MS: purity: 9596; MS (m/z): 208 (MN). - с 74U7 M-(2-aminopyrid-b-yl)-M2-(2,6- Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-dimethylphenyl)-5-fluoro-2 ,4- (3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(2-aminopyrid-6- and pyrimidinediamine (K927078) ip)-M2-(2,6-dimethinephenyl)-5-fluoro -2.4-pyrimidinediamine is obtained as a result of the reaction of M4- and -(2-aminopyrid-6-yl)-2-chloro-5-fluoro-4-pyrimilinamine and 3,5-dimethylanilic, "H NMR (0М50-в6); 5 8.33 (5, 1NU, 7.78 (i, 18, 7: 8.7 Gy), 7.29 (B5, 2H), 6.77 (Bi, 1H, 1-5 5.4 Gu, 5.61 (68 , 1), 6.47 (y, 1H, 7: 8.7 Hz), 2.22 (5, 6H); LC/MS: purity: 10095; MS (m/z): 325 (mM 74.58 MA43, 4-dichlorophenyl)-M2-(2,6- Analogous to the preparation of M4-(3-chloro-4-methoxycarboniamethyleneoxyphenyl)-5-feoro-M2-(ee) dimethyphenyl)-5-fluoro-2,4- (3-( x-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidineliamine, M4-(3,4-pyrimidinediamine (K927079) dichlorophenyl)-M2-(2,6-dimethylphenia)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of km reactions of 2-chloro-M4-(3,4-dichlorophenyl)-5-fluoro-4 -pyrimidinamine and 3,5-limethylaniline. "n -y (Se) 42) ko 60 b5

NMR (DM5O-46): 59.57(85, YIN 9518 (5, 1), 8.16 (4, 1H, 1- 3.6 Hz), 5.04 (4, MH, 1- 2.7 11) , 7.81 (a, 1, 2-27 and 9.3 Gy), 7.52 (4, 1H, 7- 9.0 Hz, 7.22 (c, 2H), 6.54 (a, 18 ,35 2 Ho), 2.17 (5, 6H); PHU/MS: purity: 9295; MS (m/z); 377 (M). 7.4.59 M2-(2,6-dimethylphenyl)-Mm4- (3,4- Analogously to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-ethylenedioxyphenyl)-5-fluoro-2,4- I|3-CM-methylamino)carbonylmethyleneoxyphenyl!-2,4 -pyrimidinediamine, M2-(2,6-pyrimidinediamine (KU27086) dimethylphenyl)-ma-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-Ma4-(3, 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidivamine and 3,5-dimethylaniline." NMR (OM50-46): 69.11 (5, 1H), 9.01 (5, IN), 8.02 (4, 1H, 7" 3.9 Hz), 7.26 (t, ZH), 7.18 (t, IN), 6.78 (4, 1H, 7 8.7 Hz), 6.49 ( 65, 1H), 4.21 (in, 4H), 2.16 (5, 6NU;

LC/MS: purity: 9795; MS (m/z): 367 (Mn. 74.60 M2-(2,6-dimethylphenyl)-5-fluoro-M4- Analogously to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2- (indoleb -yl)-2,4-pyrimidinediamine 13-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(2,6- (8927088) dimethylphenyl)-5-fluoro-M4-(inlol-6-yl )-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-(indol-b-yl)-4-pyrimidinamine and 3,5-dimethylaniline. "1 NMR (SRSI); 58.12 (б5, 1Н), 7.95 (Bv, IN), 7.92 (8, 1Н, 3- 3.3 Hz), 7.60 (8, IN, 1- 8.7 Gy), 7.19 0, IN, I 2.7 Hz), 7.15 (5, 7H), 7.07 (84, TN, 2- 1.5 and 8.1 Hz), 6.93 (5, 1H), 6.86 (be, 1H), 6.65 (5, IN), 6.54 (t, 1H), 2.19 (5,6H); LC/MS: purity; 10095; MS (m/z): 348 (MH) 7.4.81 Ма42-(M-acetylamino)pyrid-b-yl|-М2- Similar to the preparation of М4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-М2-(3,5-dimethylphenyl)-5- fluoro-2,4- 13-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(240M-pyrimidinediamine (5927092) apetylamino)pyrid-6b-yl|-M2-(3,5-dimethylphenyl)- 5-f thor-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-12-(M-acetylamino)pyrid-b-yl|-2-chloro-5-fluoro-2,4-pyrimidinamine and 3,5-dimethylaniline, "H NMR (0М5О0-46): 5 10.23 (5, 1Н)), 9.18 (5, 1Н), 8.99 (65, IN), 8.17 (t, 1НУ, 7.73 (t, 2Н ), 7.28 (5, 1), 7.25 (5, 2), 6.55 (t, 1H), 2.20 (5, ZNU), 2.17 (5, ZM);

LC/MS: purity: 8095; MS (m/z): 367 (MN). 7.4.62 2-(3,5-dimethylphenyl)-5-fluoro-M4-12-(M- |) Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-methylamino)carbonylaminopyrid- b-ily1- (3-SM-methylamico)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(3,5-2,a4-pyrimidinediamine (KU27098) dimethylphenyl)-5-fluoro-M4-|2-(M- methylamino)carbonylaminopyrid-6b-1l1-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-Ma4-12-(M-methylamino)carbonylaminopyrid-6-yl|-2,4-pyrimidinamine and 3,5 -dimethylaniline. "H NMR (PM5O-46): 6 9.73 (5, 1H), 9.26 (5, 1H), 9.21 (5, 1), 8.77 (65, HO, 8.21 (9 , 1H, 1-33 Hz 7.798, 1H, 157.5 tsu, 7.57 (IN, 22: 7.8 Hz), 7.27 (85, 2H), 6.62 (4, IN, 1-8 ,4 Hz), 6.55 (5, 1H)), 2.74 (d, ZN, I: 4.2 Hz), 2.20 (5, 6H); LC/MS: purity: 10096; MS ( m/z): 382 (MH). 7.4.63 M2-(3,5-dimethylphenyl)-5-Ffluoro-M4-H-0M- | Similar to the preparation of 2-chloro-5-fluoro-M4-12-(M -methylamino)carbonylaminopyrid-b-yl|-methylamino)carbonylindole-b-yl|-2,4-2,4-pyrimidinamine, M2-(3,5-dimethylphenyl)-5-fluoro-M4-|11-(М -methylaminocarboni l)indole-b-sc pyrimidinediamine (5927099 il)-2,4-pyrimidinesamine is obtained as a result of the reaction of M2-(3,5-dimethylifenyl)-5-fluoro-M4-c. of indole-b-yl)-2,4-pyrimidinidiamine and triphosgene. LC/MS: purity: 9290; MS (m/z): 405 o (MH). 74.64 Ma-(2-aminopyrid-b-yl)-M2-( 3-chloro-4- Analogously to the preparation of IM4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-IM2" trifluoromethoxyphenyl)-5-fluoro-2,4- 3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4 - pyrimidine iamine, M4-(2-aminopyrid-b-pyrimidinedismin (2927081) yl)-M2-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(2-aminopyrid- β-yl)-2-chloro-5-fluoro-4-nyrimidineamine and 3-chloro-4-(Che)trifluoromethoxyaniline. "H NMR (PM5O-6); 5 9.66 (5, NU, 8.94 (5, 1NU, 8.16 (4, IN, 12 3.0

Gu, 8.12 (64, 1NU, 7.65 (69, 1H, 12 9.0 Hz), 7.39 (t, 2H), 7.22 (t, 1H), 6.20 (4, 1H, ze 7.6 b

Go), 5.84 (65, 2H); LC/MS: purity: 9595; MS (m/z): 415 (MN). 74.65 M2-(3-chloro-4-trifluoromethoxyphenyl)-M4- | Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2» h-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4- I3-0M-methylamino)carbonylmethyleneoxyphenyl|-2,4 -lyrimidinediamine, M2-(3-chloro-4-pyrimidinediamine (К927085) trifluoromethoxyphenyl)- M4-(3,4-ethylenedioxyphenia)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-Ma-(3 ,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3-se chloro-4-trifluoromethoxyaniline. IN NMR (0M50-y6): and 9.56 (5, 1H), 9.28 (5, HO, 8.10 (d,

IN, 1- 3.9 Hz), 8.05 (4, IN, 1-- 2.4 Gy), 7.69 (44, IN, 3- 2.7 and 9.0 Gy), 7.34 (40, IN, 151.2 and so 9.0 Gy), 7.24 (4, 1H, 1-24 Hz), 7.12 (44, 19, 4-2 2.4 and 8.7 Gy) , 6.81 (8, EN, 1: 8.4 Hz), 4.22. (8,

Academy of Sciences); LC/MS: purity: 9095; MS (m/z): 457 (MN). 7A66 Ma-(2-aminopyrid-6-yl)-M2-(3-chloro-4- Similar to the preparation of Ma4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-methoxyphenyl)-5-fluoro-2 ,4- IZ-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(2-aminopyrid-b-pyrimidinediamine (K927082) yl)-M2-(3-chloro-4-methoxyphenyl)-5-fluoro -2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(2-aminopyrid-b-yl)-2-chloro-5-fluoro-4-pyrimidinamine and 3-chloro-4-methoxyaniline. -H NMR (PMI5O-46): 5 9.23 (5, IN), 8.68 5, 1H)), 8.09 (y, IN, 2- 3.3 Hn), 7.86 (a, 1H,1- per g), 7.46 (4, NN, 35 9.6 Hz), 7.34 (t, ZNU, 7.026, IN, 1" 9.0 Hz), 6.17 94, 1H, - s 1-2 7.2 Hz), 5.80 (t, 28), 3.78 (5, ZN); RHLMS: purity: 10095; MS (m/z): 361 (MN. 1467 M24(3-chloro-4-methoxyphenyl). M443,4- Similar to the preparation of MA-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-pethylenedioxyphenyl) -5-fluoro-2,4- (3-(M-methylamino)carbonylmethyleneoxyphenyl |-2,4-pyrimidinediamine, 142-(3-chloro-4-p » (chrymidinediamine (K927084) methoxyphenyl)-M4-(3, 4-Stylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3-chloro-4-methoxyaniline. "H NMR (OM5O-46): 5 9.15 (5, 18), 9.12 (5, 1H), 8.02 (4, INN, 1- 3.9 iv), 7.804, IN, 12 2.4 Go), 7.48 (4, 1H, 1-5 2.4 and 6.3 Gy), 7.26 (0, IN, 122.4 Go), 7.164, 1H, 3-27 and 9.3 Gy), 7.004, 1H, 1-5 8.7 Gy), 6.794, 1H, 2- 8.7 Hz), 4.22 (65, AN), 3.78 (5, ZN); (ee) LC/MS: purity: 9695; MS (m/3): 403 (MIN). 7.4.68 M2-(3-chloro-4-methoxyphenyl)-5-fluoro-1M4- | Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl) )-5-fluoro-M2- co (indolob-ip)-2,4-pyrimylindiamine (3-(m-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidnia iamine, M2-(3-chloro-4-(K927091) ssh methoxyphenyl)-5-fluoro-Ma-(indole-b-ip)-2,4-pyrmidinediamine is obtained as a result of the reaction - A (Ce) 42) ko 60 b5

(K927091) 2-chloro-5-fluoro-M4-(indol-6-yl)-4-pyrimidinamine and 3-chloro-4-methoxyaniline. N'YAME (SOS): GP 8.25 (B5, 1H), 8.03 (b5, NN), 7.89 (4, 1H, 1- 3.3 Hz), 7.82 (a, IN, 2-2.7 Gy), 7.59 (8.18, 1-8.4 HZ), 7.20 (t, 1), 7.15 (4, IN, 3 2.4 Гп), 7, 07 (vv, 1H), 6.96 (4d, IN, 12 2.1 and 8.4 Gy), 6.92 (t, 1H), 6.84 (4, IN, 2 8.7 Hz), 6.52 (t, 1H), 3.89 (5, ZN); LC/MS: purity: 9795; MS (m/z): 380 (MN). 7.4.69 M2-(3-chloro-4-methoxyphenyl)-5-fluoro-Ma. | Similarly to the preparation of 2-chloro-5-fluoro-M4-12-(M-methylaminocarbonium)aminopyryl-b-yl|-

P-(Memethylaminocarbonyl)nolol-b-yl)-2,4-pyrimidinamine, M2-(3-chloro-4-methoxyphenyl)-5-fluoro-M4-(M1-(M-2,4-pyrimidineliamine) K927100) methylaminocarbonyl)indol-b-yl|-2,4-pyrimidindiamine is obtained as a result of the reaction M2-(3-chloro-4-methoxyphenyl)-5-fluoro-M4-(indol-b-yl)-2,4- pyrimidinediamine and triphosgene followed by quenching with methylamine. LC/MS: purity: 8895; MS (m/z): 441 (MH). 7.470 Ma-(2-aminopyrid-6-1l)-5-fluoro-M2-(3- Similarly to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-hydroxyphenyl)-2,4-pyrimidinediamine (3-eM-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4-(2-aminopyrid- 6-(K927083)yl)-5-fluoro-M2-(3-thihydroxyphenyl)-2,4-pyrimidineliamine is obtained as a result of MA reaction.(2-aminopyrid-6-yl)-2-chloro-5-fluoro-4 -pyrimidinamine and 3Z-hydroxyaniline. /"H NAM? (0М5О0-а6): 59.17 (5.15, 9.13 (8, IN), 8.67 (5, IN), 8.08 (4, IN, 1- 3.0 Hn), 7.42 (t, 18), 7.35 (1.212 7.8 Hz), 7.18 (68, 1), 7.14 (in, IN, 4-72 and), 6.98 (2, 18, 1-7.8 Go), 6.31 (49,

IN, 1.2 and 6.9 Gy, 6.170, 1H, 2-7.5 Gy), 5.77 (point NN); LC/MS: purity: 10095: MS (mi): PPE (Mn. hall Ma-3-chloro-4-methoxyphenyl)»3-fluoro» Similar to the preparation of 2-chloro-5-fluoro-14х4-(2-(0М) -methylaminocarbonyl)aminopyrid-b-yl|.-

M211-(M-methylaminocarbonyl)indole-b-7,4-pyrimidinamine, M4-(3-chloro-4-methoxyphenyl)5-fluoro-M2Y-(M-yl|-2,4-pyrimylindiamine (K927094) methylaminocarbonyl)indole -b-yl|-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-(indol-6-yl)-2,4-pyrimidinediamine and triphosgene with the following quenching with methylamine. "H NMR (OMI5O-46): and 11.09 (5, 1H), 957044, 1H, 4.2.

Gy), 9.49 (5, 1H)), 8.18 (9, TA, 13.3 Hn), 7.544, 1, 1-5 8.4 Gy), 7.81 (1, I 27 Hz) , 7.30 (4, EN, 1-27 Go), 7.15 (5, 1), 6.81 (49, 1H, 2.7 and 9.0 Hyd), 6.72 (46, IN) , Re 1.8 and 5.1

Breed), 6.54 (5, 1H)), 5.74 (8, IN, 19.6 Hn), 3.62 (5, ZNU, 2.77 (d, ZY, 1- 4.5 Hn) ; PHU/MS: purity: 99925; MS (m/zu: 441 (Mn. tA M2-(3-xpor-4-methoxyphenyl)-M442.2" Analogous to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)- 5-fluoro-M2-dimethyl-3-oxo-4H-bena|1 oxazine-b- (3-(h-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(3-chloro-4-yl)- 5-fluoro-2,4-pyrimidinediamine methoxyphenyl)-Ma-(2,2-dimethylp-3-oxo-4H-benzi 1,4|oxazin-3-6-yl)-5-fluoro-2,4- ( 8927097) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-dimethyl-3-oxo-4H-benz|1,4|oxazin-6-yl)-5-fluoro-4-pyrimidinamine and 3-chloro -4-methoxyaniline. "H NMR (pM50-46): 5 10.60 (5, IN), 9.31 (5, 1HO, 9.08 (5, IN), 8.04 (0, 1H, 3 » 3.6 Gu, 7.81 (4, 1H, 7- 3.3 Hz), 7.45 (49, 1H, 5: 2.7 and 9.3 Go), 7.23 (yes, 1, 7-21 and 8.7 Gy), 7.16 (а, 1Н, and: 2.4 Hz), ши 6.93 (d, 1Н, 3- 9.0 Гн), 6.89 (8, IN , / 2 8.4 Ga, 3.76 (5, ZNU, 1.40 (5, 9H); LC/MS: purity: si 7707 o 7.43 Ma4-(3,4-dichlorophenyl)-yCh2-(2, 2-dimethyl-3-|Anapogy preparation of Ma-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-3-fluoro-M2-oxo-4H-benz(i,5)oxazin-b-yl)-5-fluoro- | I34(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinidiamic, M4-(3,4-2,4-pyrimidinediamine (927059) dichlorophenyl)-M2-(2,2-dimethyl-3-oxo-4H-benzi I Oxazine-b-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-dichlorophenyl)-5-fluoro-dpyrimidinamine and 6-amino-2,2-dimethyl -3-oxo-4H-benzi 1, oxazine. "NN NMR (OM50- du: 5 10.64 (5, 18), 10.10 (5, IN), 9.72 (5, 1H), 8.22 (4, IN, 3- 3.9 Gy ), 8.10 (5, IN), 7.74 (va, (Che) zo 1H, 72 9.0 Gy, 7.52 (d, 1H, 7: 9 Ha); LC/MS: purity: 8995 ; MS (m/z): 448 (MN). 7.44 M2-(4-chloro-3,5-dimethylphenyl)-M44(3,4- Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5- fluoro-M2-(c!ethylenedioxyphenia)-5-fluoro-2,4- (3-(Mi-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(4-chloro-3,5-pyrimidinediamine) (8927117) dimethylphenyl)-m4-(3,4-ethylenelioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is restrained in h- as a result of the reaction of 2-chloro-Ch4-(3,4-styrenedioxyphenia)-5-fluoro-4-pyrimidinediamine and 4-chloro-3,5-dimethylaniline. "H NMR (PM5O-46): 5 9.16 (in5, 2H), 8.04 (y, 1.» 3.6 Hz), 7.45 (in, 2, 7.25(t, 1H), 6.80 (a, 1H, 7 8.7 Gy), 4.21 (65, 2H), 2.22 (5, 6H); LC/MS: purity: 9195;

MS (m/zu 401 (MN).

Zo 74al5 M2-(4-chloro-3,5-dimethylphenyl)-M4-(2,2- Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-he)dimethyl-3-oxo -4H-benzi 1,4 oxazine-b-(3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M2-(4-chloro-3,5-yl)-5-fluoro-2,4-pyrimidinediamine dimethylphenyl)-M4-(2,2-dimethyl-3-oxo-4iH-benzi 1,4 |oxazin-6-yl)-5-fluoro-2,4- (K927118) pyrimidinediamine is obtained as a result of the reaction of 2-chloro- M4-(2,2-dimethyl-3-oxo-4H-benz|/1,4oxazineb-yl)-5-fluoro-4-pyrimidinamine and 4-chloro-3,5-dimethylaniline. "H YAME (0M50-465): 510.62 (5, 18), 9.32 (5, 1H), 9.11 (5, KN), 8.06 (f, 18, 1-x 3.9 Hyii), 7.46 (v, 2H), « 7.26 (49.1H, 3-24 and 8.7 Hz), 7.18 (t, 18), 6.89 (0, 1H, /- : 8.7 Hz), 2.20 (v, 6H)), 1.49 (5, NU; 20 LC/MS: purity: 9990; MS (m/z): 441 (M). -o 7.476 ( 3-M4-4(2,2-difluoro-3-oxo-4H- Analogously to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2- benzo(1,4)oxazin-b-yl )-M2-(2-0h- (3-(M-methylamino)carbonylmethyphenoxyphenyl|-2,4-pyrimidinediamine, (E)-M4-(2,2-difluoro-3- methylaminocarbonyl)-2,3» oxo- 4H-benz 1,4 |oxazin-b-yl)-M2-(2-(M-methylaminocarbonyl)-2, 3-dihydrobenzofuran-5-h z» dithiarobenzofuran-5-yl|-5-fluoro-2,4 - yl|-5-fluoro-2,4-thyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-difluoro-3-p pyrimidinediamine (4927049) oxo-AN-benzyl 1.4)oxazin-6-yl) -5-fluoro-4-pyrimidinamine and (4)-5-amino-2-(M-methylaminocarbonyl)-2,3-dihydrobenzofuran. "H NMR (0M50-46): 5 11.96 (in, 1H), 9.48 (5, 1NU, 8.92 (5, 1H), 8.06 (y, IN, 1-- 3.6 Gy), 8.01 (4, TA, 7: 4.5 Hz), 7.56 ( t, 18), 7.49 (b5, 15), 7.40 (5, 1H), 7.23 (t, 2H), 6.67 (0, IN, 1 8.7 Gy), 5.04 (44, 1H, 7: 5.7 and 6.6 Hz), 3.58 (aa, 1 HO), 3.11 (49, 1H, B- 5.7 and 6.6 Gy), 2.59 (y, ZN, 1 4.5 Ha); LC/MS: purity: 9895; MS (ee) (m/zu: 487 (MN). 174.77 4-m4-(3-chloro-4-methoxyphenyl)-M2-(2- Analogous to the preparation of Ma-(3-chloro-4-methoxycarbonylmethyleneoxyphenia)-5- fluoro-M2-co (M,M-dimethylaminocarbonyl)-2,3- (3-(M-methylamino)carbonylmethnleneoxyphenia|-2,4-pyrimidinediamine, Sk)-M4A(3-chlor-4- -y (Ce) 42) ko 60 b5 dihydrobenzofuran-5-yl|-5-fluoro-2.4-methoxyphenyl)-M2-(2-(M,M-dimethylaminocarbonyl)-2,3"dihydrobenzofuran"5-yl1-5-fluoro-pyrimidinediamine " (К927052) 2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and (1)-5-amino-72-(М,М -dimethylaminocarbonyl)-2,3- dihydrobenzofuran. "H NMR (0M5O0-4y6): 6 9.24 (5, 1H), 8.98 (5, 10), 8.01 (4, IN, 32 3.3

Gi), 7.74 (8, 1H, 2: 2.4 Hz), 7.64 (04, 1H, 127.1 and 9.0 Hn), 7.49 (5, 183, 7.19 (8 , 1H, 8.7 Hz), 7.104, 1H, 1- 8.7 Gy), 6.64 (0, 1H, y- 8.7 Gy), 5.54 (44, 1H, Te 8.7 and 7.8 Gu), 3.84 (5, ZN), 3.30 (t, 2NU, 3.08 (5, ZI), 2.86 (5, ZN); LC/MS: purity: 9395; MS (m/3): 458 (MIN), 7.48 (9 Ma43-chloro-4-trifluoromethoxyphenyl)- | Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-

М2-(2-(М, Methylaminocarbonyl)-2,3-| 5-fluoro-2,4-trifluoromethoxyphenyl)-M2-(2-(M,M-dimethylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl|-5-pyrimidinediamine (К927053) fluoro-2,4-pyrimidinediamine is obtained in as a result of the reaction of 2-chloro-M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-4-pyrimidinamine and ()-5-amino-2-(M,M-dimethylaminocarbonyl)-2,3-dihydrobenzofuran, " H NMR (0M50-46): δ 9.59 (5, 1H), 9.10 (5.1), 8.124, 1H, 2- 3.6 Gy), 8.09 (5, 1), 7, 83 (64, 1H, 18.7 Hz), 7.48 (t, 2), 7.20 (b, 1H, 2121-84 Hz), 6.67 (4, TN, 3: 8.4 Hz) , 5.58 (4, 1H, 72 8.1 Hn), 3.30 (t, 2H), 3.08 (5, ZN), 3.86 (z, ZN); LC/MS: purity: 9692 : MS (m/z): 512 (MN). 7.4.79 ()-ma-(3-chloro-4-methoxyphenyl)- M2-12- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro -M2-(3-12-(M-(M-methylaminomethylene)-2,3- morpholino)ethyleneoxy |phenyl|-2,4-pyrimidinediamine, as a result of the reduction of ()-M4-(3- dihydrobenzofuran-5-yl -5-fluoro- 2,4-chloro-4-methoxyphenyl)-M2-12-(M-methylaminocarbonyl)-2,3-dihydrobenzofuran-5-yl|-5-fluoropyrimidinlyamine (K927045) 2,4-pyrimidinediamine with borane:methyl sulfide is obtained (-)-M4-(3-chloro-4-methoxyphenyl)-

M2-(2-(M-methylaminomethylene)-2,3-dihydrobenzofuran-5-yl|-5-fluoro-2,4-pyrimidinediamine. 1H NMR (0M50-46); 5 9.22 (5, 1) , 8.92 (5, IN), 8.01 (f,1H, 32 3.6 Hz), 7.78 0, 18, 1-30

Hz), 7.64 (t, 1H), 7.43 (05, 1H), 7.16 (49, 1H, 1-: 2.4 and 10.5 Hz), 7.08 (y, 1H, 1: 8.7 Gy), 6.57 (4, 1H, 12 8.1 Hz), 4.77 (t, 1NU, 3.82 (5, ZNU), 3.11 (44, IN, 3- 9.3 and 8.7 Hn), 2.85 (yes, IN, /- 7.5 Giz), 2.66 t, 2H), 2.30 (4, ZN); LC/MS: purity: 9595; MS (m/z): 229M'); 430 (MN). 7.4.80 5-fluoro-M2-|20E)-4(IV, 25, 5K)- Similar to the preparation of M4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-5-fluoro-M2-menthyloxycarbonyl)-2,3" ( 34(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrumidinediamine, 5-fluoro-M2-12(B)-dihydrobenzofuran-5-yl1-M4-(4-418, 25, 58.)-menthyloxycarbonyl)-2, 3-dihydrobenzofuran-5-171-M4-(4-isopropoxyphenyl)-isopropoxyphenyl)-2,4-pyrimidineliamine | 2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M44(4- (8927062) isopropoxyphenyl)-4-pyrimylinamine and 5-amino-(2(K)-(IR, 25, 5K)-menthyloxycarbonyl ) |- 2,3-dihydrobenzofuran.. LC/MS: purity: 9395; MS (m/z: 563 (МН). 7.4.81 М4-(2,2-difluoro-3-oxo-4Н- Analogous to the preparation of М4-(3-chloro-4-methoxycarbonylmethyleneoxyphenyl)-3-fluoro-М2- benzene 1,4 |oxazin-b-yl)-M2-(E)AE, |3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4.(2,2-difluoro-3-25, 58)- methyloxycarbonyl) -2,3-oxo-4H-benz| 1 Poxazin-6-yl)-Mm2-Y2(B)-4(B, 25, 58)-menthyloxycarbonyl)-2,3- dihydrobenzofuran-5-1l1-5-fluoro-2,4- lihydrobenzofuran-5-yl |-5-fluoro-7,4-pyrimidinediamine is obtained as a result of the reaction 2- Ha! pyrimidinediamine (8927063) chloro-M4-(2,2-difluoro-3-oxo-4H-benz| 1,4 |oxazin-b-yl)-5-fluoro-2,4-pyrimidinamine with 5- Ge) amino- H(8)-1(1E, 258, 52) methyloxycarbonyl)-2,3-dihydrobenzofuran. LC/MS: purity: 93925; MS (m/z)y: 612 (MN).

Preparation of salts based on bis-ZMAg products 7482 Salt of p-toluenesulfonic acid M2-(3,5- Dry reactor with a magnetic stirrer, rubber membrane and feed hole M; (Che) dimethoxyphenyl)-M4-(2,2-dimethyl-3 -oxo- | fill M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethyl-3-oxo-4H-benz| 1,4 |oxazin-6-yl)-5- 4H-benz 1 ,4|oxazine-b-ip)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine (0.220 g, 0.5 mmol) and MeOH (15 mL). To this suspension of pyrimidinediamine (K927070) p-toluenesulfonic acid monohydrate (0.095 g, 0.5 mmol) is added at 0 "C for 2-3 (22) minutes. After adding p-topotoluenesulfonic acid monohydrate, the suspension turned into a clear solution. After stirring the solution for 5 minutes, it is concentrated, or using a rotary evaporator, and the precipitate is recrystallized with NINEU As: hexanes (1:1:5 ml; by volume) to obtain the salt of p-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)-M4 -(2,2-dimethyl-3-oxo-4H-benzi 1,4 |oxazin-b-yl)-5-fluoro-2,4- i. pyrimidinediamine. Alternatively, the precipitate is immersed in EOH and precipitated with n-

ZB of hexanes or ethyl ether to obtain the salt of p-toluenesulfonic acid M2-(3,5- (ee) dimetaoxyphenyl)-M4-(2,2-dimethyl-3-oxo-4H-benzi 1 4|oxazine-b-1l) -5-fluoro-2,4-pyrimidinediamine in the form of an amorphous solid. "H NMR (0M5O-46): 5 10.60 (5, 1H), 10.07 (vv, 1H), 9.60 (b5, IN), 8.15 (4, 1H, 1- 5.1 Hn) , 7.44 (44, 2H, 34-:1.2 and 6.0 Gy), 7.28 (t, 18), 7.16 (t, 1), 7.10 (44, 2H, )- 1.2 and 6.0 Gy), 6.854, 1H, 1-8.4 Gy), 6.74 (i, 2H, 2.8

Gsh), 6.19 0, 1Н,2- 2.8 Hz), 3.64 (5, 6Н)), 2.289 (5, ЗН), 1.41 (5, 6Н); LC/MS: purity: 10099;

MS (m/z: 440 (MA as the starting base). " 7.4.83 Salt of methanesulfonic acid M2-(3,5- Analogously to the preparation of the salt of p-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2,2- dimethoxyphenyl)-M4-(2,2-dimethyl-3-oxo- with 4H-benzi 1,oxazin-b-yl)-5-fluoro-2,4-methanesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethyl.-3-oxo-4H.pyrimidinediamine ( 2927071) benz|1,4)oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine is supported as a result of the reaction M2-h (3,5-dimethoxyphenyl)-M4-(2,2-dimethyl-3-oxo -4H-benzyl 1,Hoxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine and methanesulfonic acid. LC/MS: purity: 9825; MC (m/z): 440 (MH"; as the starting base). 7.4.84 Salt of benzenesulfonic acid M2-(3,5- Analogously to the preparation of the salt of p-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2, 2" dimethoxyphenyl)-M4-(2,2-dimethyl-3-oxo-|limethyyl-3-oxo-4H.benzi 1,4|oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine, salt

AN-benzi 1,4|oxazine-6-12)-5-fluoro-2,4- benzenesulfonic acid M2-(3,5-dimethoxyphenial)-MA-(2,2-limethyl-3-oxo-4H- (ee ) pyrimidinediamine (2927072) benzyl 1, Noxin-6-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethyl-3- oxo-4H-benz|1,4|oxazin-b-yl)-5-fluoro-2,4-co| of pyrimidinediamine with benzenesulfonic acid. Shk YAM (OM50-46): 5 10.61 (5, 1), 10.00 -y 7 42) ko 60 b5 іб5, 1), 9.57 (p5, IN), 5.159, 1H, 1-45 P), 7.57 (t, 2H), 7.28 (t, ZN), 7.16 (p8, 1), 6.86 (4.1, 1- 8.4 Sp), 7.76 (65, TR) , 6.17 (f, IN, 12 2.1 Gy), 3.64 (5, BNO, 1.41 (5, 6); LC/MS: purity: 10099; MS (m/z): 440 ( МН"; and the original base). 7.4.85 Tihydrochloride M2-(3,5-dimethoxyphenyl)- Similar to the preparation of the salt of p-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2,2-

M442,2-dimethyl-3-oxo-4H-dimethyl-3-oxo-4H-benz| 14 Ooxazin-6b-yl)-5-fluoro-2,4-pyrimidinediamine, hydrochloride YM2- benzo(i, Yaoxazin-6-1l)-5-fluoro-2,4-(3,5-dimethoxyphenyl)-M4- (2,2-dimethyl-3-oxo-4H-benz| I, 4|oxazin-6b-yl)-5-fluoro-7,4-pyrimidinediamine (K927073) pyrimidinediamine is obtained as a result of the reaction M2-(3,5- dimethoxyphenyl)-M4-(2,2-dimethyl-3-oxo-2H-benz|1,4|oxazann-b-yl)-5-fluoro-2,4-pyrimidinediamine with hydrogen chloride (4M, dioxane). LC/MS: purity: 10095; MS (m/z): 440 (MN; as starting base). 7.4.86 Salt of Ri.-camphorsulfonic acid M2-(3,5- | Analogously to the titration of the salt of p"-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2,2- dimethoxyphenyl)-Ma4-(2,2- dimethyl-3-oxo- | dimethyl-3-oxo--H-benz | 1,4 |oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine, Ri salt - 4AN-benz ( i, 4oxazin- 6-yl)-5-fluoro-2,4-camphor sulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethyl-3-oxo-4H-pyrimidinediamine (2927074) benzyl1,oxazin-b-yl )-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethyl-3-okeo-4H-benz| 1,4 |oxazine-6- yl)-5-fluoro-2,4-pyrimidinediamine with ОЙ -camphorsulfonic acid. "H NMR (PM 5O-46): δ 10.59 (in, 1H), 10.10 (B, IN), 9.65 ( 68, IN), 8.17 (4, 1H, 2- 4.5 Hz), 7.27 (t, 1H), 7.15 (iv, 18), 6.86 (4, IN, I» 8 ,4

HB, 6.74(4, 1 H, ze 2, Go), 6.19 (t, 1H), 3.64 (5, 6H), 2.89 (f, 1H, 32 11.7 Hm), 2.66 (t, 18), 2.48 (t, 2H), 2.40 (d, IN, 7: 14.7 Hyd), 2.23 (1, 1H, 7» 3.3 and 18 ,3 Hn), 1.94 (t, 1), 1.85 (t, 2NU, 1.41 (5, 6H), 1.25 (t, 2H), 1.05 (5, ZNU, 0, 75 (5, ZN); LC/MIS: purity: 10095; MS (m/z): 440 (MN"; as the starting base). 75 7.4.87 Salt of p-toluenesulfonic acid M2-(3,5-) Similar to the preparation of the salt p-toluenesulfonic acid 142-(3,5-dimethoxyphenyl)-iM4-(2,2-dimethylphenyl)-M4-22,2-dimethyl-3-oxo-dimethyl-3-oxo-4H-benz | 1,4 oxazine- b-yl)-5-fluoro-2,4-pyrimidinediamine, salt of p-4H-benz and ,NHoxazin-b-yl)-5-fluoro-2,4-ltoluenesulfonic acids M2-(3,5-dimethylphenyl)-144 -(2,2-dimethyl-3-oxo-4H-pyrimidinediamine (5927075) benzyl 1,4 |oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction M2-(3,5- Dimethiaphenyl)-M4-(2,2-dimethyl-3-oxo-4H-benzyl)-5-fluoro-2,4-pyrimidinediamine with p-toluenesulfonic acid. "H NMR (PM5O-46): 5 19.65 (5, 1H)), 9.95 (B5, 1NI), 9.40 (B5, 11), 8.13 (4, 1H, 12: 4 .8 Gy), 7.45 (4, 2H, 12: 7.8 Gy), 7.26 (t, 1), 7.14 (05, 19), 7.099.2H, 1- 7.5 Gsh) . ; LC/MS: purity: 10096; MS (m/z); 408 (MN; as a starting point). 7.4.88 Salt of benzopsulfonic acid M2-(3,5- Analogously to the preparation of p-toluenesulfonic acid salt M2-(3,5-dimethoxyphenyl)-M4-(2,2-dimethydphenyl)-M4-(2,2-dimethyl-3-oxo - dimethyl-3-oxo-4H-benzi 1,4 (oxazin-b-yl)-5-fluoro-2,4-pyrimidinedigmine, salt

AN-benz|! 4 |oxazin-6-yl)-5-fluoro-2,4-benzenesulfonic acid M2-(3,5-limethylphenyl)-im4-(2,2-dimethyl-3-oxo-4H- pyrimidineliamine (2927076) benzi1,4 |oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction M2-(3,5-dimethylphenyl)y-M4-(2,2-dimethyl-3-oxo-4H.benz 4 Oxazine-b-1l)-5-fluoro-2,4-pyrimidinediamine with benzenesulfonic acid. YUM? (0М50-а6): 6 10.67 (5, 1H), 1012 sem

What (B5, 1H), 9.555, IN), 8.159, IN, 3-48 Hz), 757 (t, 28), 7.28 (t, YAN), 7.11 (b5, ZN), 6.90 ge) (4 ,18, 2-84 Hz), 6.66 (68, 1), 1.40 (5, 6H); RHLMS: purity: 10096; MS (m/z): 408 (MN; as the starting base), 7.4.89 Salt of p-toluenesulfonic acid M4-(3- Analogously to the preparation of salt of p-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)"M44/2,2- chloro-4-methoxyphenyl)-5-fluoro-M2-(indole-|dimethyl-4H-benz|1,4-oxazin-3-oxo-6-yl)-5-fluoro-2,4-pyrimidinediamine, salt p - b-yl)-2,4-pyrimidinediamine (K927087) toluenesulfonic acid M4-4(3-chloro-4-methoxyphenyl)-5-fluoro-Mo-indole-b-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-(se) (indol-b-yl)-2,4-pyrimivindiamine and p-toluenesulfonic acid salts... LC/MS: purity: 10095; MS (m/z): 384 (MH; as the starting base). (e") 7490 Salt of p-toluenesulfonic acid M4-(3,4" Analogously to the preparation of the salt of p-toluenesulfonic acid M24(3,5-dimethoxyphenyl)-M4-(2 ,2-ethylenedioxyphenyl)-5-fluoro-2-|3-(M-dimethine-4H-benz| and ,4-oxazin-3-oxo-6-1l)-5-fluoro-2,4-pyrimidinedigmine, salt (5927090) methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-13-(М- with methylamino)carbonylmethyleneoxyphenia|-2,4-pyrimidinediamine and salt n. toluenesulfonic acids. /"H NMR (0M50-46): 5 9.99 (B, IN), 9.79 (05, 1H)), 8.14 (4, 1H, 7-5 (ee) 4.8 g), 7.974, 1, 3-5.1 Ha), 7.14 (46, 2H, with- 2.4 and 9.0 Gy), 7.25 (t, 18), 7.14 (t, 5H), 6, 80 (4.1, 25 8.4 Gy), 6.64 (t. 1H), 4.36 (5, NU, 4.22 (5, NI), 2.64 (4, ЗН, 1- 4 .8 Go), 2.28 (5,

ZN); LC/MS: purity: 10095; MS (m/z): 426 (MN; as starting base). Synthesis of anilines and products mono 5MAg

TA 2-isopropoxy-3-nitropyridine Solution of 2-bromo-5-nitropyrylline (1.0 g, 4.9 mmol), potassium t-butylate (6.9 ml, 6.9 mmol, M « solution in THF), and isopropyl alcohol (75 ml) is heated at a temperature of 752C for 2 days. The reaction mixture is concentrated in a vacuum, and the precipitate is suspended in water and treated with ultrasound at room temperature for several minutes. c The product in the form of a beige solid is collected by filtration, 1InYaMe (SOSIzh 8

GU 9.06 (0, 2- 3.0 Gy, IN), 8.31 (440, 7- 3.0 and 9.3 Go, 1), 6.73 (4, 12 9.3 Gu, IN ), 5.43 (apipei, i? 1-5.7 Hn, IN), and 137 (0.3-63 Gy, 1H). 7.4.92 5-amino-2-isopropoxypyridine Similar to the preparation of 4-aminophenoxyacetate, hydrogenation of 2-isopropoxy-5-nitropyridine is carried out to obtain 5-amino-2-isopropoxypyridine. /H NMR (SOSISU: 5 7.65 (4, 1-27 Hu, 1NU, 7.01 (44, 12 3.0 and 8.7 Hz, 1), 6.54 (8, 159.0 Gy, EN), (ee) 5.13 (dpvitee, 1- 6.6 Hz, 1H), 3.20 (B5, 2H), and 1.32 (9, y- 6.6 Gu, 6). 7.4. 93 2-chloro-5-fluoro-M4-(2- Analogous to the preparation of 2-chloro-M4-43,4-ethylenelioxyphenial)-5-fluoro-4-pyrimidinamine, co isopropoxypyridin-5-1l)-4- 2-chloro -5-fluoro-M4-(2-isopropoxypyridin-5-yl)-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-feorpyrimidine and 5-amino-2-isopropoxypyridine. /H NMR (SOCI3): 5 8.30 (f, 1-3.0 Hz, 18), 8.06 (a, 1-21 Hz, 1NU, 6.81 (5, EN), 6.75 ( b, 42 9.0 Hz, 1H), 5.27 (dshteb, 4- 6.6 Hu, 1H), and 1.35 (40, 1: 6.6 Hn, 6H) 7.4.94 3-chloro- 4-(M-morpholino)nitrobenzene A mixture of 2-chloro-4-fluoronitrobenzene (1.36 g, 7.72 mmol) and morpholine (8.0 mL, 90 mmol) was heated at 802 for 3 hours.The reaction mixture was poured into a vol. (150 mL), and the product as a yellow solid was collected by filtration.IN NMR (SOCI3): 6 8.264j, 1-5 3.0 Hn, 1NU, 8.11 (00.2 3.024 9.3 Hz, IN) , 7.05 (60, 1: 8.7 Gy, 1 NO), 3.91-3.87 (t,

AN), and 3.23-3.19 (t, AN). 7.4.95 3-chloro-4-(M-morpholino)aniline To a solution of 3-chloro-4-(M-morpholino)nitrobenzene (1.0 g, 4.1 mmol) in ethanol/water (70 ml, 2: 1) first add iron powder (1.4 g, 25 mmol), and then MH.SI (0.46 g, 8.6 mmol). The reaction mixture: stirred at room temperature for 10 minutes, 706 then heated at 702C for 1.5 hours. After cooling to room temperature, the reaction mixture is filtered through celite, and the precipitate formed on the filter is washed with methanol. As a result of concentration of the filtrate in vacuum, a white solid is obtained, which is dissolved in stylacetate and washed with ManSO" (89) and brine. The organic layer was dried (Me50O), filtered, and concentrated in vacuo to give the product as a white solid. In 'YAMmR (SRSISU: b 6.98-6.91 (t, H), 6.82 (05, 1H), 6.67-6.61 (t, 1H), 3.90-3.82 ( t, 4H), and 3.02-2.90 (t, 4H). 7.4.96 2-chloro-Ma-(3-chloro-4-(04-) Similar to the preparation of 2-chloro-Ma-(3,4 -ethylenedioxyphenyl)-5-fluoro-4-pyrimylamine, morpholino)phenyl|-5-fluoro-4- 2-chloro-M4-13-chloro-4-(M-morpholino)phenyl|-5-fluoro-4-pyrimidinamine obtained in pyrimidineamine as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-(M-morpholino)aniline.

NMR (PINE: 5 8.09 (8, 722.4 Hz, IN), 7.75 (0.2- 3.0 Hz, 1H), 7.55 (da, 2- 2.7 and 8.7 Hz,

IN), 7.32 (0.2-8.7 Hz, 1H), 6.92 (b5, IN), 3.99-3.92 (t, 4NI), and 3.21-3.14 ( t, 48). 74.97 3-chloro-4-isopropoxynitrobenzene In contrast to the preparation of 2-isopropoxy-53-nitropyridine, 3-chloro-4-isopropoxynitrobenzene is obtained as a result of the reaction of 3-chloro-4-fluoronitrobenzene with isopropanol and potassium t-butylate. 268, ,3- 301), 8, ,

P b iyu TN NMR (SOSIZ): 6 8.26 (d, 1- 3.0 Hz, 1), 8.11 (84, 1-30 and 8.7 Gu, 1H), 6.97 (d, 3- 8 .7 Gy, 18), 4.71 (dshipiei, /- 6.0 Gy, IN), and 1.43 (4, 7-60

Gi, bN). 74.98 3-Chloro-4-isopropoxyaniline Similarly to the preparation of 3-chloro-4-(M-morpholino)aniline, 3-chloro-4-isopropoxynitrobenzene is reduced to obtain 3-chloro-4-isopropoxyaniline. others

NMR (0M5O0-yv): 65 6.80 (y, 1: 8.7 Hz, 1H), 6.59 (y, 7-24 Gy, IN), 6.43 (44, 32: 3.0, 8.7 Hz, se - - shi 1H), 492 (B, 2), 4.24 (dme, 2- 5.7 Hz, 1), and .18 (9.7- 5.7 gy, CH) . Ge) 174.99 2-chloro-M4-(3-chloro-4-isopropoxyphenia)- | Similarly to the preparation of 2-chloro-M44(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, 5-fluoro-4-pyrimidinamine 2-chloro-M4-(3-chloro-4-isopropoxyphenyl)-5-fluoro- 4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-isopropoxyaniline. /N YAM? (SOS 8 8.04 (4, 32 3.0 Pi, 1), 7.61 (d, 32 2.7 Gy, IN), 7.48 (4d, 1 3.0 and 8.7 Hz, 1H ), 6.99-6.93 (t, 2H), 4.52 (dchitek, 12 6.0 Hz, 18), 1.37 (d,3- 6.0 Gy, 68); I9E NMR (282 MGy, SOS): - re) 158.12; LC/MS: purity: 9495; MS (m/z): 317 (MN). b 74100 5-Amino-2-(MM-Borane-methyl sulfide complex (4.0 ml, 43 mmol) is added to a suspension of 2-HOM,M-dimethylaminomesyl)benzofuran dimethylamino)carbonyl|-5-nitrobenzofuran (1.0 g , 43 mmol) in anhydrous TIF (10 ml).

The reaction mixture is heated under reflux for 3 hours. After cooling, the solvent is removed in vacuo to form a gel-like solid. Cold (0 2) methanol (50 ml) is carefully added dropwise, and the resulting mixture is heated at 50 "C for 30 minutes, keeping a clear yellow solution.

The solvent is removed in vacuo, the resulting solid is suspended in methanol (50 mL) and HCl (1.5 mL, 4M in dioxane) is added. After heating at 80 °C for 30 minutes, the solvent was removed under reduced pressure to give an amorphous solid. The solid was dissolved in methanol (20 mL) and ammonia (2M in methanol) was added until the solution became alkaline. After dissolution with dichloromethane, a precipitate (50 ml) is formed. As a result of filtration and concentration, the intermediate 2-(M.Medimethylaminomethyl)-5-nitrobenzofuran is obtained in the form of a yellow oil (1.0 g), which is "used without further purification. To the suspension of the intermediate 2-( M,M-limethylaminomethyl)-5-nitrobenzofuran (1.0 g) in methanol (degassed, 60 ml) is added -

Ma»52O4 (0.50 u) and 1095 Ra/C (100 mg). The reaction mixture is moved in a hydrogen atmosphere for 10 hours. The solid substance is removed by filtration through the auxiliary filter material Celite, and the precipitate formed on the filter is washed several times with metacol. As a result of concentration, a dark yellow oil is obtained. The product, 5-amino-2-(М,М- dimethylaminomethyl)benzofuran, obtained after purification by column chromatography on silica gel (mobile phase: 095 io 595 methanol (contains 2M MH» udichloromethane). IN ' NMR (СО5ОР): 8 7.24 (y, 1Н, 12 8.7 Hn ), 6.91 (d4,1H,3: 2.4 Hz), 6.76 (a, 1H, 32 2.4 and 8.7 Hyd), 6.65 (5, 1), 3.87 ( 5, 2H), 2.48 (5, 6H). (ee) Reactions of bis-5MAg and subsequent reactions of molten CO) M2-(2-carboxy!-2,3- As a result of the reaction M4-(3-chloro-4 -trifluoromethoxyphenyl)-5-fluoro-M2-(2-methoxycarbonyl-

Reaction of dihydrobenzofuran-5-yl)-M4-(3-chloro-4-2,3-dihydrobenzofuran-5-yl)-2,4-pyrimidinediamine and lithium hydroxide (SHON) in THF:H»O and trifluoromethoxyphenyl)-5 -fluorine-2.4- at room temperature followed by oxidation with an aqueous solution of 2M HCl to obtain -y 42) 60 b5 pyrimidinediamine (K926957) -trifluoromethoxyphenyl)-5-fluoro-2,A-pyrimidinedimin. 1H NAM (OM5O-yr): 5 9.62 (5, TN), 914 (5, 1H), 8.11 (40, 1- 3.6 and 7.5 Hz, 2NU, 7.81 (44, 15 3.0 and 9.3 Go, 181), 7.49-7.44 (t, 2), 7.22 (44, 352.4 and 8.1 Hz, 1H), 6.724, 1- 9, 0 Hz, IN), 5.21-5.13 (t, AND NO), 3.48 (44, 1- 10.5 and 15.6 Hz, 1H), 3.17 (Chd, 12 6.0 and 15.6 Hz, INU; LC/MS: purity: 9895; MS (m/z): 486 (МН. 2 7.4.102 (x) M4-(3-chloro-4-trifluoromethoxyphenyl)-. | Similar to preparation IM4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-im2-|3-(015-5-fluoro-M2-(2-(0M-2,3-morpholino)carbonylmethyleneoxyphenyl-2,2 -pyrimidinediamine, as a result of the reaction of dihydroxypropylamino)carbonyl-2,3- racemic M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(2-methoxycarbonyl-2,3- dihydrobenzofuran-5-yl|-2 ,4-lihydrobenzofuran-5-yl)-2,4-pyrimidinediamine and racemic 2,3-dihydroxypropylamine pyrimidinediamine (8926958) obtain a mixture of two racemates M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(2 -(M-2,3-dihydroxypropylamino)carboyl-2,3-dihydrobenzofuran-5-yl|-2,4-pyrimidinedismine.

IN NMR (prison: 6 8.06 (4, 422.4 Go, 1H), 7.92 (4, 42: 2.4 and 4.2 Hz, 1H), 7.68 (04, 15 3.0 and 9.3 Hn, IN), 7.41-7.37 (t, 19), 7.34-7.29 (t. 1H), 7.26-7.19 (t, 1), 6.82 ( 4.1-8.7 Hz, 1H), 5.18-5.11 (t, 1H), 3.74-3.66 (t, 1H), 3.60-3.52 (t, IN) , 3.50-3.42 (t, 2), 3.38-3.35 (t, 1H), 3.21 (d4, 1- 7.2 and 13.5 Hz, 1H); I9E NMR ( 282 MHz, STO): -169.15, 60.23; RU/MS: purity: 9895; MS (m/z): 559 (MAH). 7.4.103 (ur m4-(3-chloro-4-trifluoromethoxyphenyl )- | Similar to the preparation of M4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-M2-|3-40h- 5-fluoro-M2-(2-0M4-2-morpholino)carbonylmethyleneoxyphenyl|-2, 4-pyrimidinediamine, CE) M4-(3-chloro-4-hydroxyethylamino)carbonyl-2,3-trifluoromethoxyphenyl)-5-fluoro-M2-(2-(M-2-hydroxyethylamino)carbonyl-2,3-dihydrobenzofuran -5-yl|-2,4- dihydrobenzofuran-5-17)-2,4-pyrimidinediamine is obtained as a result of the reaction of racemic pyrimidinediamine (2926959) M4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-( 2-methoxycarbonyl-2,3-dihydrobenzofuran-5-yl)-2,4-pyrimidinediamine and ethanolamine. IN 'YAMe (SRO): 6 8.65-8.05 (t, 1), 7.94-7.90 (t, 1H), 7.68 (4, 7--3.0 and 9.3 Gu, IN), 7.39-7.35 (t, 1H), 7.31 (44, 72 1.2 and 8.7 Gy, IN), 6.829, 12 8 Hz, 15, 5.18-5.10 (t , 18), 3.64-3.21 (t, 7NU; 19E NMR (282 MGy, SI., ODR): -169.19, -50.24; LC/MS: purity: 9896; MS (m/ z): 529 (МН). 7.4.104 (i) ma-(3-chloro-4-trifluoromethoxyphenyl)- | Similar to the preparation of M4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-M2-( 13-(M-5-fluoro-ych2-(2-(0M-2-tihydroxyethyl-M.morpholino)carbonylmethyleneoxyphenyl-2-4-trimidinediamine, racemic M4-(3-chloro-4-methylamino|carbonyl-2,3- trifluoromethoxyphenyl)-5-fluoro-M2-(2-methoxycarbonyl-2,3-dihydrobenzofuran-5-yl)-2,4-dihydrobenzofuran»5-yl|-2,4-pyrimidinediamine and M-methylethanolamine are restrained as a result of the reaction of rgomide (2) MA. pyrimidinediamine (K926960) (3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-M2-(2-0M-2-hydroxyethyl-M-methylamino |carbonia- 2,3-ditihydrobenzofuran-5-ip |-2,4-pyrimidinediamine. RHLIS: purity: 9595; MS (m/z): 543 (МН. 7.А.105 МА4(3-chloro-d-trifluoromethoxyphenyl)-5-А similar to the preparation of 14-(3,5-dichloro-4-hydroxyphenyl)-5-difluoro-M2-H3-(M-fluoro-M2-12-(M-isopropylamino)carbonyl- | morpholino)carbonylmethyleneoxyphenylI-2,4-pyrimidinediamine, (4) M4-(3-chloro-4-. with 2,3-dihydrobenzofuran-5-yl|-2,4- trifluoromethoxyphenyl)-5-fluoro-M2-12- (M.isopropylamino)carbonyl-2.3-dihydrobenzofuran- o pyrimidinediamine (KU26961) 5-yl|-2,4-pyrimidinediamine is restrained as a result of the reaction of racemic M4-(3-chloro-4-trifluoromethoxyphenium)-5-fluoro-M24(2 -methoxycarbonyl»2,3-digylrobenzofuran-5yl)-2,4-pyrimidinedismine and isopropylamine. LC/MS: purity: 9496; MS (mu: 526 (MN). 74196 5-fluoro-M4-(2-isopropoxypyridin-5-yl)-.- | Similar to the preparation of MA-(4-chloro-3-methoxyphenia)-5-fluoro-M2-13 -(M-

M2413-(M-methylamino)carbonylmstyleneoxypheny)-2,4-pyrimidinediamine, 5-fluoro-M4-2-(Che) methylamino)carbonylmethyleneoxyphenyl|- | isopropoxypyridin-5-yl)-M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4- 2,4-pyrimidinediamine (KU26962) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4-42-He isopropoxypyridine- of 5-yl)-4-pyrimidianamine and 3-(M-methylamino)carbonylmethyleneoxyaniline in isopropanol. YIN YAM? (РМ5О-ав): 6 9.34 (5,

IN), 9.225, 1H)U, 8.60-8.56 (t, 1H)), 8.07 (4, 3.6 Hn, 1H), 8.02-7.92 (t, 2H), 7.36 (05, IN), h- 7.258, 8.4 Hz, IN), 7.08 (1-81 Gu, 1NU, 6.72 (y, 2- 8.7 Hz, 18), 6, 46 (ad, 5 21 and 8.1

Ty, 1 N), 5,17 (dmipiee, 7: 6,3 Gu, NN). 4.34 (z, 2H), 2.63 (4, /-: 3.9 Gy, ZN), 1.27 (y, 1- 6.6 Hz, sem 6Nu; LC/MS: purity; 9395; MS (m/z): 427 (MH). 7.4.107 Ma-(3-chloro-d-methoxyphenyl)-5-fluoro-M2- | Similar to the preparation of MA-(3,5-dichloro-4-hydroxyphenyl)- 5-fluoro-M2-(34(M-(se) (3chcm-morpholino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3-chloro-4- hydroxyethylamino)carbonylmethyleneoxy | methoxyphenyl)-5-fluoro-ych2- (3(0M-2-hydroxyethylamino)carbonylmethyleneoxyphenyl |-2,4-phenyzh)-2,4-pyrimidinediamine (2926963) pyrimidinediamine is obtained as a result of resection of M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2- (3-Methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and ethanolamine IN NMR (pp): 6 7.90 (4.1: 3.3 Hn, 1H), 7.76 (0.2: 3.3 Gy, IN) , 7.54 (ai, 7- 2.1 and 8.7 Hz, 1H), « 7.34-7.29 (t, 1), 7.17-7.14 (t, 2H), 7, 03 (d, 7-8.7 Hz, IN), 6.62-6.56 (t, 1NI), 4.39 (5, 28), 3.87 (5, ZN), 3.62 (i ,3- 5.7 Hz, 2H), 3.40 (6, 12: 5.7 Gy, 2H); 19E NMR (282 MHz, SIZOUU: « -v 168.65; EX/MS: purity: 9795; MS (m/z): 462 (MAH). c 7.4.1198 (7) ma43-chloro -4-methoxyphenyl)-5-fluoro- | Similarly to the preparation of M4-(3,5-dichloro-4-hydroxyphenyl)-5-fluoro-M2-13-(M-h M2-134(M-2,3-morpholino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, ( 5) M4A3-chlor-4-y - dihydroxypropylamino)carbonylmethylene | methoxyphenyl)-5-fluoro-M2-/3-(0M-2,3-dihydroxypropylamino)carbonylmethyleneoxyphenyl|-2,4-oxyphenyl)-2,4-pyrimidinediamine pyrimidinediamine is obtained as a result of the reaction of M4-(3-chloro-4- methoxyphenia)-5-fluoro-Mao" (8926964) (3Z-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and racemic 2,3-dihydroxypropylamine. IN YAM, (0M50-46): 5 5.35 (5, 1H)), 5.23 (5, IN), 8.09 (d, 75 KG,

NU, 7.87-7.78 (t, 2H), 7.70 (49, 122.4 and 9.0 Gy, IN), 7.32-7.27 (t, 29), 7.15- 7.08 (t, 28), (ee) 6.48 (ad, 2- 2.4 and 90 Gy, IN), 4.38 (5, 2NI), 3.82 (5, ZNU, 3.55 -3.21 (t, 5H). 3.08-2.98 (t,

ZNU; LC/MS: purity: 9895; MS (mz): 493 (M NN. ko 744109 M2M4-bis(4-benzyloxy-3-chlorophenyl)-3- | Similar to the preparation of M2,Ma-Bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine . -dichloro-5-fluoropyrimidine and 3-chloro-4-benzyloxyaniline. 1 yaYAMe (0M5O-ar): 59.43 (5, 1H), 9.27 (5, 1H), 8.09 (y, 22:42 Hz, 1H), 7.76 (44, 12 2 and 5 ,4 Hz, 2H), 7.62 (ad, 12 2.4 and 9.6 Hz, IN). 7.48-7.29 (t, 11), 7.17 (4, 7 8.7 Gu, 19), 7.09 (4.72 8.7 Hz, 1H), 5.18 (5, 2H ), 5.12 (5.2H); LC/MS: purity: 9790; MS (m/z): 562 (MN). 7410 М4-(4-benzypoxy-3-chlorophenyl)-5-fluoro- Similar to the preparation of М4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-I3-(М-

Mm2-I34(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(4-benzyloxy-3-methylamino)carbonylmethyleneoxyphenyl- | chlorophenyl)-5-fluoro-M2-|3-(M-methylamino)carbonylmethyleneoxyphenyl|-72,4-pyrimidinediamine 2,4-pyrimidinediamine (K926966) is obtained as a result of the reaction of M4-(4-benzyloxy-3-chlorophenyl)- 2-chloro-5-fluoro-4-pyrimidinamine and 3-C(M-methylamino)carbonylmethyleneoxy aniline. IN NMR (0M5O0-ab): 59.64 (5, 1H), 9.535, 1), 8.13 (y, 1-42 Hz, IN), 7.99-7.94 (t, 11), 7 .81 (9, 1-24 Hz, 18), 7.6784, 31- 2.7 and 8.7 Hz, 1H), 7.48-7.07 (t, 9), 6.52 (44, 1- 1.8 and 8.1 Hz, IN), 5.18 (5, 28), 4.35 (8 2), 2.62 (y, /- 4.8 Hz, ZN); LC/MS: purity: 9896; MS (m/z): 509(MN). tally M4-4(3-chloro-4-methoxyphenyl)-M2-13-(M- Analogous to the preparation of M4-(3,5-dichloro-4-hydroxyphenia)-5-fluoro-M2-13-(M- cyclopropylamino) carbonylmethyleneoxy|morpholino)carbonylmethyleneoxyphenyl/|-2,4-pyrimidinediamine, M4-(3-chloro-4-phenyl|-5-fluoro-2,4-pyrimidinediamine methoxyphenyl)-M2-13-(M-piclopropylamino)carbonylmethyleneoxyphenyl-5 -fluoro-2,4- (8926967) pyrimidinediamine is obtained as a result of the reaction of M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenia)-2,4-pyrimidinediamine and cyclopropylamine. /IN

NMR (0M80-y6): δ 9.88 (5, 18), 9.70 (in, 1H), 8.17 (y, 1: 4.8 Hz, IN), 8.06 (y, 1: 3.9 Hn, 18), 7.79-7.76 (t, 1H), 765:(aa, 1-2, and 81 Hz, 1), 7.2257.11 (t, AN), 6.57- 6.52 (t, IN), 4.32 (in, 27), 3.82. (5, ZN), 2.69-2.61 (t, 1H), 0.63-0.56 (t, 2), 0.47-0.43 (t, 2H); LC/MS: purity: 9296; MS (m/z): 459 (Mn. 74412 M2-(3-chloro-4-hydroxy-5-methylphenyl)- Similar to preparation 144 44-chloro-3-methoxyphenyl)-5-fluoro-M2-(34(1M .

M443-chloro-4-methoxyphenyl)-5-fluoro-2,4- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M24(3-chloro-4-hydroxy-5-pyrimidinediamine (KU26968) methylphenyl)-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4- pyrmidinediamine is obtained as a result of the reaction of 2-chloro-M44(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and 3-chloro-4-hydroxy-5-methylaniline. TN YAM (0M50-yr): 6 9.49 (5, 1NU, 9.17 (5, 1H), 8.66 (t, 1H), 8.07 (4.4-4.2 Gu, 1H) ), 7.71-7.62 (t, 2H)), 7.46 (5, EN), 7.18 (66, IN), 7.09 (d, 1-90, IN), 3.82 (5, ZN), 2.09 (5, ZN); LC/MS: purity: 9595; MS (m/zu: 410 (MN). 7.a4413 M-(3-chloro-4-methoxyphenyl)-M2-(34(M- Analogous to the preparation of M4-(3,5-dichloro-4-hydroxyphenyl)-5 -fluoro-m2-(3-(M-cyclobutylamino)carbonylmethyleneoxy|morpholino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4-43-chloro-4-phenyl|-5-fluoro-2.4-pyrimidinediamine methoxyphenyl)-M2-13- (M-cyclobutylamino)carbonylmethyleneoxyphenyl|-5-fluoro-2,4- (K926969) pyrimidinediamine is obtained as a result of the reaction M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2- and (3-methoxycarbonylmethyleneoxyphenyl)- of 2.4-pyrimidinediamine and cyclobutylamine

NMR (OMBO-arU 6 9.52 (5, 1H)), 9.37 (5, 18), 8.21 (0, 72: 7.8 Hz, 19), 8.01 (8, 13.3 Hz, 1H), 7.798, 1-3.3 Su, 1H), 7.59 (44, 12 2.4 and 9.6 Sn, IN), 7.27-7.22 (t, 2H), 7 ,16-7.08 (t, 2H), (o) 5.504, 12.4 and 8, Hz, IN), 4.32 (5, 215), 4.24 (a, 8.1 Hz, IN) , 3.82 (5, ZA), 2.18-2.05 (t, 2H), 2.00-1.89 (ti, 2H), 1.64-1.53 (t, 2H); RHLMS: purity: 9595; MS (m/z): 4730 МН. 7.4.114 MA442,2-difluoro-3-oxo-4H- Similar to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-4M-benz| 1,4 Zoxazin-6-yl)-M2-(3,5-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, I44-12,2-difluoro-3-oxo-4H-dimethoxyphenyl)-5-fluoro-2 ,4-benz 1,4 |oxazin-b-yl)-M2-(3,5-dimethoxyphenyl)y 5-fluoro-2,4-pyrimidinediamine is obtained in (Ce)pyrimidinediamine (5926970) as a result of the reaction of 2-chloro-M4- (2,2-difluoro-3-oxo-4H-benzi I Poxazin-6-yl)-5-fluoro-4-pyrimidinamine and 3,5-dimethoxyaniline. 1INNMR (0М5О-а6): 8 1.92 (5, 180, 9.55 (v, EN), (e") 9.09 (5, IN), 8.12 (а, 1- 6.0 Hn, 1 ), 7.52-7.46 (t, 2H), 7.22 (6, 3-87 Hz, INNU, 6.91 (а, 1-24

Those 1H), 6.05 (5.32 2.4 Hz, 115), 3.61 (5, 6H); 192 YAM? (282 MGu, OM5O»avu: «164.56, - che 76.64; LC/MS: purity: 985; MS (m/z): 448 (MN). 7.4115 M2-(3-chloro-4-hydroxy -5-methyphenyl)- Similar to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-4(M-He

M442,2-difluoro-3-oxo-4H. methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M2-43-chloro-4-hydroxy-5-z5 benzo(i,oxazin-b-yl)-5-fluoro-2,4- methylphenyl)-M4-(2 ,2-difluoro-3-oxo-4H.-benzi 1,4 uxazin-b-1l)-5-fluoro-2,4-pyrimidinlyamine and pyrimidinediamine (KU26971) are obtained as a result of the reaction of 2-chloro-M4-(2, 2-difluoro-3-oxo-4H-benz|1,4)oxazine-6-1l)-5-fluoro-4-pyrimidenamine and 3-chloro-4-hydroxy-5-methylaniline. IN NMR (0М50-а6): 6 11.95 (5, IN), 9.50 (5, IN), 9.00 (5, EN), 8.56 (z, IN), 8.09 (4 , 1- 3.6 Hz, IN), 7.57 (4, 72-24 Hz, 18), 7.49-7.40 (t, 2NU, 7.24 (5, EN), 7.22-7.19 (t, 18), 2.07 (in, ZNU; 192 NMR (282 MGy, OM5O- a6u: -165.46, -76.51; LC/MS: purity: 9495; MS (m/z): 453 (My. « 7.4.116 Ма4(3-chloro-4-methoxyphenyl)-М2-(3-chloro- -5-methylphenyl)-5-fluoro-2.4-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinidiamine, М4-(3-chloro-4- - pyrimilindiamine (К926972) methoxyphenyl)-М2-(3-chloro-4- methoxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-h pyrimidine and 3-chloro-4 -methoxy-5-methylaniline. 1H NMR (PM50-46): δ 9.38 (in, 1), "n » 9.25 (5, 18), 8.094, 12 3.6 Hz, 1H), 7, 70 (4, 72:24, 1H), 7.66-7.58 (t, 7H), 7.33 (4.32 24 Hz, 1H) 7.114, 2- 8.7 Hz, 1), 3.83 ( 5, ZN), 3.66 (5, ZN), 2.14 (5, ZNU; RH/MS: purity: 9495;

MS (m/z): 424 (MN). 74417 Ma-(3-chloro-4-isopropoxyphenyl)-5-fluoro- | Similarly to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro- M2-134(M. o 142-13-(M-methylamino)carbonylmethyleneoxyphenium |-2,4-pyrimidinediamine, M4-(3-chloro- 4- methylamino)carbonylmethyleneoxyphenyl)- | isopropoxyphenyl)-5-fluoro-M2-|3-(M-methylamino)carbonylmethyleneoxyphenyl 1)-2,4-t 2,llurimidinediamine (K926973) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4- isopropoxyphenia)- -y 42) 60 b5

5-fluoro-4-pyrimidinamine and 3-(M-methylamino)carbonylmethyleneoxyaniline. IN NMR (RM5O-46): 6 9.30 (5, 1), 9.21 (5, IN), 8.08 (4, 7- 3.6 Ha, 1H), 7.95-7 .88 (t, IN), 7.8I-7.79 (t, EN). 7.69 (44, 2- 3.0 and 8.7 Hz, 18), 7.32-7.28 (pt, 2NI), 7.13-7.07 (t, 2), 6.49- 6.44 (t, 1H), 4.57 (after 7-6.0 Hz, 1H)), 4.34 (5, 2), 2.63 (4, 1 4.8 Hz, Z), 1 .26 (4.1-6.9 Ha, 6H);

LC/MS: purity: 9995; MS (m/z): 461 (MN). 7.4.118 Ma-(3-chloro-4-methoxy-5-methylphenyl)-5- | Similarly to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro-Ich2-Y3-(M-fluoro-M2-(3-((M-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine, M4-( 3-chloro-4-methoxy-5-methylamino)carbonylmethyleneoxyphenyl| reactions of 2-chloro-M4-(3-chloro-4-methoxy-5-methylphenyl)-5-fluoro-4-pyrimidinamine and 3-(M-methylamino)carbonylmethyleneoxyaniline.

IN NMR (COZOYU): 5 8.01 (0.3-5.4 Hz, 1H), 7.60 (y, 72 2.4 Hz, NN), 7.40-7.29 (t, 2H) ), 7.10-7.04 (t, 2NU, 6.89-6.84 (t, 1H), 4.38 (in, 2H), 3.79 (5, ZNU, 2.79 (5, ZN), 2.25 (5, ZNU; PH/MS: 70 purity: 9695; MS (mu: 441MN. 7.4.119 1m44(3,4-dichlorophenyl)-5-fluoro-M2-(indole- | Similar to the preparation of M4-(4-chloro -3-methoxyphenyl)- 5-fluoro-M2-134(0M-b-yl)-2,4-pyrimidinediamine (К926975) methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3-chloro-4-methoxy -5-methylphenyl)-5-fluoro-M2-(3-(1h-methylamino)carbonylmethyleneoxyphenyl-72,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M44(3,4-dichlorophenyl)-5-fluoro-4- pyrimidineamine and b-aminoindole. !H NMR (STOY): 5 7.99 (4.1- 2.4.1), 7.91 (4.1- 3.6

Gy, IN), 7.72 (y, 3-3.0 and 8.7 Gy, 1H), 7.60 (y, 3-:1.2 Cy, IN), 7.48 (4, 3- 8.7 Go, IN), 7.25 (4.15 90 go, 1NO, 7.17 (9, 12 3.0 Hz, TA), 7.06 (49, re 1.8 Hz, 1 NO) . M44(3-chloro-4-methoxyphenyl)-5-fluoro-M2- 2,4-pyrimidinediamine methylamino)carbonylmethyleneoxyphenyl I|-2,4-pyrimidinediamine, M443-chloro-4-(8926976) methoxyphenyl)-5-fluoro-M2-(indol-b-yl)-2,4-pyrimidinediamine is obtained as a result reaction of 2-chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrmidinamine and b-aminoindole. (5, 1H), 9.02 (v, 10), 8.05 (j, 1: 3.6 Hz, CEJU, 7.85 (4.152, gy, 1), 7.81-7.76 (t , 2), 7.36 (4, 1-87 Hz, 1), 7.21 (8,121.8 Hn, 1H), 7.19. 7.15(t, 1), 7.034, 3- 8.7 Go, 1H), 6.30 (5, IN), 3.81 (5, ZNU; LC/MS: purity: 9395; MS (m/z): ZVOMN. 744121 Mach2,2-difluoro-3-oxo- 4H" Prepares similarly 5-fluoro-1H4-(3-hydroxyphenyl)-M2-14-(3-phenyl»1,2,4-oxadiazole-3»benzyl1,4|oxazin-6-yl)-5-fluoro-M2.-yl )methyleneoxyphenyl)-2,4-pyrimidinediamine, M4-(2,2-difluoro-3-oxo-4H-benz(1,4|oxazin-6-(indol-b-yl)-2,4-pyrimidinediamine yl) -5-fluoro-M4-(indole-6-14)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4- (8926977) (2,2-difluoro-3-oxo-4NI-benz| | Yaoxazin-b-yl)-5-fluoro-4-tyrimidine and b-aminoinlolol. si

IN NMR (РМ5О-4р): 6 11.91 5. 1Н), 10.83 (5, 1Н). 9.48 (5. 1H), 8.91 (in, 1H), 8.09 (4, 1: 3.6 Go)

Gy, 15), 7.84 (b5, 15), 7.68 (44, 1-3.0 and 93 Gy, IN), 7.54-7.51 (t, 19), 7.34 (f , 4-8.7 Hz, 1H), 7.208, 1H), 7.18-7.14 (tv, 2), 6.32-6.28 (ti, 1H), LC/MS: purity: 9895; MS (m/z); 427 (M). 7.414122 М4-(3-chloro-4-methoxyphenyl)-М2-12-(М,М- | Similar to the preparation of 5-fluoro-М4-(3-hydroxyphenyl)-М2-14-(3-phenyl-1,2, 4-oxdiazol-5-dimethylaminomethylubenzofuran-5-yl|-5-|yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, 1M442,2-difluoro-3-oxo-4H-benz|1,4Zoxazin-b- (Te) fluoro-2,4-pyrimidinediamine (926978) yl)-5-fluoro-M2-(indol-b-ia)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4A-(3-chloro-4-methoxyphenyl )-5-fluoro-4-pyrimidinamine and 5-amino-2-(M,M-dimethylaminomethyl)benzofuran. NMR (0Mm50-4x 59.27 (5, 1H), 9.15 (5, 1H), 8.06 (y, b» 1:36 Hz, 1), 7.85 (5.18), 7.79 (d.35-3.0 Hz, 1H), 7.69-7.63 (t, 1H), 7.35 (B5, 1H), 7.07 (4, 1-8.7 Gu , 1NI), 6.59 (5, IN), 3.83 (5, ZNU, 3.56 (5, 7NI), 2.21 (z, NU; RH/MS: purity: 9795; or

MS (nav: 443 (MH), 74123 Ma-(2,2-difluoro-Z-oxo-4H- Analogously to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-H4-(3-phenyl-1, 2,4-oxadiazol-5-se benz|1,oxazin-6-yl)-M2-12-(MuM-yl)methyleneoxyphenia)-2,4-pyrimidinediamine, M4-(2,2-difluoro-3-oxo -4 H-benzP, "oxazin-b-dimethylaminomethyl)benzofuran-5-yl|-5- | 1l)-M2-(2-(M,M-dimethylaminometnya)benzofuran-5-1l)-5-fluoro-2 ,4-pyrimidinediamine with fluoro-2,4-pyrimidinediamine (2926979) is obtained as a result of the reaction of 2-chloro-M4-(2,2-difluoro-3-oxo-4H-benzyl 1,4|oxazin-b-yl)- 5-fluoro-4-pyrimidinamine and 5-amino-2-(M,M-dimethylaminomethyl)benzofuran. LC/MS: purity: 9995; MS (m/z)y: 483 (MN). 74424 M4-(3,4-dichlorophenyl)-m2-12-(M,M- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-im2-(4-(3-phenyl-1,2,4- oxadiazole-5-dimethylaminomethyl)benzofuran-5-yl-5-|yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M4-4(3,4-dichlorophenyl)-M2-12-0M,M-" fluoro-2, 4-pyrimidinediamine (К926980) dimethylaminomethyl)benzofuran-5-yl1-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidinamine and 5 -amino-2-(M,M-dimethylaminomethyl)benzofuran. IN yaYAME (SOSI3): 6 7.99 (05, IN), 7.89(0, 3224 Hz, - s 1NU 772 In 24 Gu, 1NU, 7.43 (0, 3-2 8.7 Gy,, 1), 7.40-7.33 (t, 2NI), 7.26 (49, /-: 1.8 and 8.7

Hz, 18), 6.97 (z, IN), 6.75 (4.12 2.4 Gy, 1NU, 6.58 (5, IN), 3.67 (z, 2H), 2.38 ( z, 6H); I9E NMR m (282 MHz, SOSIZu: -47438; LC/MS: purity: 9495; MS (m/z): 445 (M-1). "» Z 7.4.125 Sh2-(3- chloro-4-methoxyphenyl)-M442.2" Analogous to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-m2-(4-(3-phenyl-1,2,4-oxadiazole-5-difluoro-3-oxo) -H-benzi 1,4 |oxazin-6-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, IM2-(3-chloro-4-methoxyphenyl)-M4-(2,2-difluoro-yl)-5-fluoro -2,4-pyrimidinediamine 3-oxo-4H-benz| and, oxazit-b-yl)y-5-fluoro-2,4-pyrimidinediamine is obtained as a result (K925981) of the reaction of 2-chloro-5-fluoro-M4- (2,2-difluoro-3-oxo-4H-benzi 1,4 |oxazin-6-ip)-4-pyrmidinamine (ee) and 3-chloro-4-methoxyaniline. NR NMR (OM5O-iv): 5 12 .07 (5, TJ), 10.09 (5, 18), 9.75 (5,

ENU, 8.20 (4, 224.2 Ti, 1NU, 7.75 (4, 12 2.4 Hz, IN), 7.52 (b5, 1H), 744-734 (t, 2H), 7.274, ke Sho 328.7 Hz, 1NU, 7.03 (d,1-9.3 Hz, 1H), 3.77 (5, ZMI); RH/MS: purity: 9696; MS (m/3u 453 (Se) 42) ko 60 b5

МШТ- и (ShttiaIRVA- :3:5:5:-77т1ч81йЙЙ020(2520--025Ш602-2052625202-202Ш5202Ш05-20ШШШ202Ш2Ш25202Ш2ШО0ШЗ20- 7.А126 M4-(2,2-dimestil-3-oxo-4H)) -M4-(3-Hydroxyphenyl)-M2-(44(3-phenyl-1,2,4-oxadiazol-5-yl)-5-fluoro-1,2-yl)methyleneoxyphenyl 2,4-pyrimidinediamine, M4-(2,2dimethyl-3-oxo-4H-benz| I,oxazine-(indole-b-yl)-2,4-pyrimidinediamine b-yl)-5-fluoro-M2-( inlol-b-yl)-2,4-pyrimylindiamine is obtained as a result of the reaction of 2-chloro- (K926982) M4-(2,2-dimethyl-3-oxo-4H-benzi I Yaoxazin-b-11)-5-fluoro -4-pyrimidinamine and 6-aminoindole. 1!YAM?(0MI8O-αv): 5 10.81 (5, TEO), 10.54 (in, NN), 9.24 (in, IN), 8.81 (5, 1H), 8.03 (4.35 3.3 Hz, 1H), 7.81 (B5, IN), 7.45-7.38 (li, IN), 7.34-7.31 (p. 20, 7.21-7.14 (t, 28), 6.83 (0.190 Hn, 18), 6.28 (d. 1» 2.4 Gy, 1H), 1.38 (5, ZNU; LC/MS: purity: 9896; MS (m/33: 419 (Mn. 7.4127 Ma-2,2-difluoro-3-oxo-4H-) Analogously to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2 -(4-(3-phenyl-I,2,4-oxadiazole-5-benz I oxazineb-1l)-M2-(2-(M,M - yl)methyleneoxyphenyl|-2,4-pyrimidinediimine, M4-(2,2-difluoro-3-oxo-4H-benzi 1,4|oxazine-b-dimethylaminocarbonyl)-2,3-1l)-Mm2-(2 -(M,M-dimethylaminocarbonyl)-2,3-dihydrobenzofuran-5-1l|-5-fluoro-2,4-dihydrobenzofuran-5-yl|-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2- chloro-M4-(2,2-lifluoro-3-ocoo-4 NU pyrimidinediamine (5926983) benzyl, Yoxazin-6-yl)-5-fluoro-4-pyrimidinamine and 5-amino-2-0Ch,M- dimethylaminocarbonyl )-2,3-dihydrobenzofuran. IN YaMe (OM50-av): 8 12.09 (5, 18), 10.25 (5, 1H), 9.59 (v, NU, 8.15 (4, 5-5 3.9 Hz, IN ), 7.52-7.39 (p, ZA), 7.26 (d, 3-8.7 Hz, 1), those (y, 1 8.4 Gu, 1), 6.69 (4, 12 8.7 Hu, IN), 5.64-5.57 (t, 1H), 3.43-3.27 (t, 2H), 3.06 (5,

ZN), 2.85 (5, ZN); LC/MS: purity: 9695; MS (m/z3): 5010MN U. 74128 M4-(2,2-difluoro-3-oxo-4H- Analogously to the preparation of 5-fluoro-MA-(3-hydroxyphenyl)- M2-I4-(3-phenyl-1 . 1,Cpoxazine-b-methoxy-5-trifluoromethylphenyl)-2,4-yl)-5-fluoro-M24(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine is obtained as pyrimidinediamine (KO26984) as a result of the reaction 2-chloro-M4-(2,2-lifluoro-3-oxo-4H-benzyl E,4)oxazine-6-1l)-5-fluoro-4-pyrimidinamine and 3-methoxy-5-trifluoromethylaniline. IN NMR (0M50-46): 6 11.92 (5, 1), 9.61 (5, 1H, 9.50 (5, IN), 8.18 (4, 7- 3.6 Hz, 115, 7.65 (5, 1H), 7.59 (5, 1), 7.48-7.41 (t, 2H), 7.22 (8.15 8.7 Hz, IN), 6.71 ( b5, 1H), 3.70 (in, ZNU; IUE NMR (282 MHz, OM5O-40): - 163.55, -76.50, -61.83; LC/MS: purity: 9895; MS (m /z): 486 (MN). 7.441129 7m2-(3,5-dichlorophenyl)-M4-(2,2-lifluoro-3- | Similar to the preparation of 5-fluoro-IH443-hydroxyphenyl)-M2-(4-(3 -phenyl-1,2,4-oxadiazole-5-oxo-4H-benz|!oxazin-b-yl)-5-fluoro-|yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M2-(3,5- dichlorophenyl)- M4-(2,2-difluoro-3-oxo-2,A-pyrimidinediamine (К926985) AP-benz(1,4|oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine is obtained in as a result of the reaction of 2-chloro-M4-(2,2-difluoro-3-oxo-4H-benz 1, oxazin-b-yl)-5-fluoro-4-pyrimidinamine and 3,5-dichloroaniline. 1H NAM (OM5Ocha6) 6 11.95 (05, TEO, 9.65 (y, 1- 3.3 Gy, 2H), 8.19 (4, 72: 3.9

Hz, 1H), 7.7 (d, 221.8 Hz, ZNU, 7.01-7.35 (t, 2), 7.27 (d, 12:9.3 Hz, 1H), 6.99 (b , 12 1.8 Gu, 1H); 192 NM (282 MG, OM5O-46): -163.24, -76.23; LC/MS: purity: 9299; MS (m/z): 457

And (m). Gee)

Al M4-(3-chloro-4-(M-morpholino)phenyl-M2- | Analogously to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-M2-144(3-phenyl-1,2,4-oxadiazole- 5-(3,5-dimethoxyphenyl)-5-fluoro-2,4-yn)methyleneoxyphenia-7,4-pyrimidinediamine, M4-(3-chloro-4-(M-morpholine)phenyl|-5-fluoro-pyrimidinediamine (2926986) M2-(3,5-dimethoxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-(M-morpholino)phenyl|-5-fluoro-4-pyrimidinamine and 3,5-dimethoxyaniline

NMR (0M50-46): 6 9.80 (08, 1H), 9.53 (05, TO, 8.16 (y, 15 4.2 Hz, 1H), 7.78-7.71 (t, 28), (Che) 7.194, 12 8.7 Ha, IN), 6.81 (5, 2НУ6.16-6Л1 (t, 1), 3.75-3.71 (t, 4Н), 3.63 (z, 5H)), 2.96-2.91 (t, 4H); LC/MS: purity: 9595; MS (m/z); 460 (MN). Ф 7.4.131 m4-(3-chloro-4-0M-morpholino)phenyl|-5- Similar to the preparation of 5-fluoro-M4-(3-hydroxyphenyl)-m2-14-(3-phenyl-1,2,4 -oxadiazole-5-fluoro-M2-(3-methoxy-5-yl)methyleneoxyphenyl|-2,4-pyrimidinediamine, M4-|3-chloro-4-0M-morpholino)phenyl|-5-fluoro» h- trifluoromethylphenyl )-2,4- M2-(3-methoxy-5-trifluoromethylphenyl)-2,4-pyrimidinediamine is restrained as a result of the reaction pyrimidinediamine (K926987) 2-chloro-M4-|3-chloro-440M-morpholino)phenyl-5- fluoro-4-pyrimidinamine and 3-methoxy-5-trifluoromethylaniline. 1NYMe (rM50-a5): 6 9.53 (5, 1H)), 9.45 (5, IN), 8.15 (d, 2- 3.6 Gv, s 1), 7.77-7, 73 (t, 2H), 7.64-7.57 (t, 21), 7.10 (4, 1: 8.7 Hz, 1H), 6.72 (65, 1H), 3.76-3.70 (t, 3o TN), 2.95-2.91 (t, 4H); 192 NMR (282 MHz, OM8O-y5); 163.57, -61.62; LC/MS: purity: (ge) 9995; MS (m/z): 498 (МН), 7.4.132 Salt of p-toluenesulfonic acid M4-(3- Analogously to the preparation of p-toluenesulfonic acid salt M2-(3,5-dimethoxyphenyl)-M4-(2,2-chloro-4 -methoxyphenyl)-5-fluoro-M2-(3-4(M- | dimethyl-4H-wenzi I, 4-oxazin-3-oxo-6-yl)-5-fluoro-2,4-pyrimidinidiamine, salt p - methylamino)carbonylmethyleneoxyphenyl-|toluenesulfonic acid M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-13-0h-" 7.4-pyrimidinediamine (8926989) methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction М4-(3-chloro-4-methoxyphenyl)-5-fluoro-М2-|340М»- methylimino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine and toluenesulfonic acid monohydrate. TN YAM (0М50-ав): 5 9.91 (B5, 1), 9.65 (B5, 1Н), 8.16 (d, 12: 4.5

Ty, IN), 8.02-7.94 (t, 1H)), 7.78 (d, 22: 2.7 Gy, 1NU, 7.64 (dy, 1: 2.7 and 90 Hz, 1 ), 7.45 (d, 1-5 t 8.1 Gy, 2NU, 7.22-7.06 st, 6H), 6.63-6.56 (,t, 1H), 4.34 (in, 2H )), 3.83 (5, ZN), 2.63 (y, 1-5 4.5 a Go, ZN), 2.28 (5, ZN). 7.4.133 Mm4-(3-chloro-4-methoxyphenyl)-M2-(3,5- Similar to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-(M-dichlorophenyl). - 5-fluoro-2,4-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3-chloro-4-pyrimidinediamine (KU26990) methoxyphenyl)-M2-(3,5-bichlorophenyl)-5-fluoro- 2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-Ma-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyramidinamine and 3,5-lichloroaniline. (se) 1H NMMR (OM5O- 4): 5 9.68 (5, 1H), 9.53 (in, IN), 8.16 (4, 7- 3.9 Hz, 1 H), 7.69 (4, 12 1.8 Gy, -y 42) 60 b5

2H), 7.66-7.58 (t, 2H), 7.13 (0, 39.3 Hz, 18, 7.01 (5-21 Gy, EN), 3.83 (5, ЗН); LC/MS: purity: 9756; MS (m/z): 415 (MH). 7.А4зА M (3-chloro-4-methoxyphenyl)-М2-(3,5- Anapogic to the preparation of M4-(4-chloro- 3-methoxyphenyl)-5-fluoro-M2-13-(M-dimethylphenyl)-5-fluoro-2,4-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, I44-(3-chloro-4-pyrimidinediamine (K926991) )U methoxyphenyl)-Mm2-(3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(3-chloro-4-methoxyphenyl)-5-fluoro-4- pyrimidineamine and 3,5-dimethylaniline. TN NMR (0M50-465): 5 10.10 (in, 114), 9.79 (in5, 1H), 8.21 (0, 224.8 Hz, IN), 7 ,71(4.1: 2.4 Hz, IN), 7.59 (44, 7 2.4 and 9.0 HY, 180, 7.14(4.4- 90 Hz, 18), 7.09 (B5 , 28), 6.65 (5, 1H), 3.85 (5, ZNU, 2.16 (5, 6H); LC/MS: purity: 9995; MS (m/z): 374 (MN). 7.441135 M4 -(3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-(M- (3-methoxy-5- trifluoromethylphenyl)-2,4-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine . 3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and 3-methoxy-5-trifluoromethylaniline. /H NMR (OM50-46): 69.52 (5.180), 9.40 (5, NN), 8.14 (8, 13.9 Hz, 19), 7.72 (4, 3: 2.4 Hz, IN), 7.68 (4th, 1- 2.7 and 9.0 Hz, 1), 7.64-7.60 (t, 1), 7.59-7.55 (t, 1H), 3 .84 (5, ZNM), 3.72 (5, ZN); LC/MS: purity: 9596; MS (m/z: 444 (MN). 7.4.136 Mma4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(4-chloro-3-methoxyphenyl)-5-fluoro -M2-(3-(M-(3,4,5-trimethylphenyl)-2,4-methylamino)carbonylmethyleneoxyphenium|-2,4-pyrimidinediamine, M4-(3-chloro-4-pyrimidinediamine (К926993) methoxyphenyl)- 5-Fluoro-M2-(3,4,5-trimethylphenyl)-2,4-pyrimidinediamine is obtained in the Nile River as a result of the reaction of 2-chloro-MA4-(3-chloro-4-methoxyphenyl)-5-fluoro-4 -pyrimidinamine and 3,4,5-trimethylaniline. 1N NMR (OM5O-4f): δ 9.23 (65, 1H), 8.91 (b, 1), 8.04 (y, /- 3.6 G , 1H), 7.78-7.66 (t, 2NI), 7.22 (5, 2H)), 7.07 (y, 1 8.7 Hz, EN), 3.83 (5, ЗН) ), 2.12 (8, 6NU, 2.03 (5,

ZN); RHLMS: purity: 9895; MS (m/z); 388 (MN). 7.4.137 M4-(2,2-dimethyl-3-oxo-4H. Similar to the preparation of Ma-(4-chloro-3-methoxyphenyl)-5-fluoro-M2-13-(M-benz| 1, oxazine-b) -yl)-5-fluoro-M2-(3,4,5-|methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidineliamine, M4-(2,2-dimethyp-3-oxotrimethylphenyl)-2,4-pyrimidinediamine 4H-benzi 1,4|oxazine-6-1l)-5-fluoro-M2-(3,4,5-trimethylphenyl)-72,4-pyrimidinedimine (8926994) is obtained as a result of the reaction of 2-chloro-M4-(2 ,2-dimethyl-3-oxo-4H-benz| and 4|oxazin-b-yl)» of 5-fluoro-4-pyrimidinamine and 3,4,5-trimethylaniline, IN YAM (0М50-а6):6 10, 57 (5, 1), 9.24 (5, IN), 8.78 (5, 18), 8.02 (4, 4- 3.9 Hz, 1H), 7.31 (46, 7- 2 ,1 and 8.4 Hz, 1H), 7.26-7.22 (t,

ZI), 6.86 (4, 7-8.7 Gu, 1 H), 2.11 (5. 6H), 2.02 (5, ZNU, 1.40 (5, 6H); LC/MS: purity: 9995;

MS (ma): 422 (MN). 5-dtor-Ma41(M- To a suspension of 5-Fluoro-M4-CI H)-indole-b-iya|-M2-(3,5-dimethoxyphenyl)-2,4-pyrimidinediamine urine methylaminocarbonium nndol-b-ily- M2- (0.045 mg, 0.12 mmol), tristylamine (0.025 He) (3,5-dimethoxyphenyl)-2.4- ml, 0.12 mmol) is added to THF (0.75 ml) at a temperature of 0 "С . 4095, 1.5 ml), stirred for 5 minutes and diluted with water. The aqueous solution was extracted with ethyl acetate, the solvent was evaporated, and the residue was subjected to chromatography (silica gel;

RT then 2-55 2M MNuUMeON in RT) to obtain 5-fluoro-M4-P1-(M-(Che)methylaminocarbonylindol-b-yl|-M2-(3,5-dimethoxyphenyl)-2,4-pyrimidinediamine. IN NMR (pM50-a6): 6 10.90 (b5, IN), 9.62 (B, IN), 9.49-9.42 (t, PN), 5.08 (4, 32 3.3 Gy , IN), 7.40 (e") (Bv5, MN), 7.35 (8, 72 8.7 Hz, 1NU, 7.30 (6, 2: 2.7 Hz, 1H), 7.09 (09, 7- 1.5 and 8.7 Gy, 19), 6.49 (5, 152.4 Hz, TN), 6.41-6.36 (t, 18), 6.29 (4, 2: 2.4 Hz, 1), 3.69 (5, 6H), 2.47 (y, 1 4.2 Go, 38); h-

LC/MS: purity: 9495; MS (m/z); 437 (MN). n Synthesis of anilines Ha 7.4.4139 2-chloro-b-methyl-4-nitrophenol M-chlorosuccinimide is added to a suspension of commercially available b-methyl-4-nitrophenol (59, 32.6 mmol) in water (300 ml) at room temperature (8.7 g, 32.6 mmol), and then with an aqueous solution of 5M potassium hydroxide (13 ml, 65.2 mmol). After stirring at room temperature for 2 hours, the resulting mixture was oxidized with 2M HCl (pH 22) and extracted with ethylene acetate (3 x 200 ml). The organic phase is separated, washed with brine, diluted (Ma»5O)), concentrated, and the obtained residue is purified by flash chromatography (EC Ac:n-hexanes 15 : 85; by volume), obtaining 2-chloro-b-methyl- 4- nitrophenol (3.7 5, 6096). "H NMR. (OM5O-ab): 8 10.84 (IN, 5), 8.20 (IN, 4, 1- 3.3 Hz), 8.13 « ana, hy, 1- 0.6 Gb ), 2.39 (ZB, 5); LC/MS: purity: 96.6995. 744140 4-amino-2-chloro-b6-methylphenol 2-chloro-b-methyl-4-nitrophenol (2.5 8, 13.32 mmol) was dissolved in crystallized ASON-c (22 ml), and iron powder (2.23 g, 40 mmol) was added. The mixture was heated at a temperature of 90 C with mechanical stirring for 2 hours, then cooled to room temperature and diluted with EOAc (200 ml). The summate was filtered through a 2 pad of Celite. The filtrate was washed with brine, dried (Ma2504) and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel with SNI" to retain 4-amino-2-chloro-b -methylphenol (1.03 g, 5099), "H NMR. (0M50-46): 5 5.02 (IN, 8, 1» 0.9 Hyd), 6.47 (1H, 4, 1-23, Gy), 638 (1 H, 6, 2-24 Gy) , 4.74 (2Н, 5), 2.16 (ЗН, 5). hall 3-chloro-4-methoxy-5-methylnitrobenzene To a solution of 2-chloro-b-methyl-4-nitrophenol (1.2 g, 6.5 mmol) in acetone (10 ml), add (ee) potassium carbonate (1.34 g, 9.75 mmol) followed by dimethyl sulfate (1.33 mL, 7.8 mmol).

The mixture is stirred under reflux conditions for 2 hours. Then ammonium hydroxide (1 ml) is added and the mixture is heated under reflux for 30 minutes. The mixture is cooled to room temperature, and the solution 42) 60 b5 is removed under vacuum. The residue was poured into water, saturated with sodium chloride, and the resulting solid was filtered to give the desired substance 3-chloro-4-methoxy-5-methylnitrobenzene (1.1 g, 8496). "H NMR. (M5O-46): 6 8.28 (IN, 4, 2-2 2.7 Go), 8.24 (1H, di, 4-2.7 Hz, 1 0.75 Hn), 3.95 (ZN, 4, 1- 0.9 Gy), 2.48 (ZN, a, 1- 0.9 Hz; LC/MS: purity: 9895. c 7.4.142 3-chloro-4-methoxy -5-methylaniline 3-chloro-4-methoxy-5-methylnitrobenzene (1.1 g, 5.4 mmol) is dissolved in crystallized

ASOH (9 mL), and iron powder (0.917 g, 16.4 mmol) is added. The mixture is heated at a temperature of 90 °C under mechanical stirring for 2 hours, then cooled to room temperature and diluted with EtOAc (200 ml). The mixture is filtered through Celite. The filtrate is washed with brine, dried (Ma»5Og) and concentrated in vacuo. The residue clarified by means of chromatography on silica gel with

SNHSI, for obtaining 3-chloro-4-methoxy-5-methylaniline. N YAM (OM5O-46): 6 6.51 (1H, 4, 12 2.7 Gy), 6.41 (IN, 4, 15 1.8 Hz, 1- 0.9 Gy), 5.11 (2H, 5), 3.68 (ZH, a, 1- 0.9 Hyd), 2.21 (H, 53; LC/MS: purity: 9595. 7.4.143 (t) 2-ethoxycarbonyl-2- methyl-b-nitro-3- | Mixture of potassium fluoride (FC) 1.8 g, 32.4 mmol), DMF (10 ml), distyl-2-bromo-2» oxo-4H-benz and Foxazine methylmalonate ( 3.2 g, 12.9 mmol) and 4-nitro-2-aminophenol (2 g, 12.9 mmol) are stirred for 16 hours, then poured into water and extracted with BYU As,

The extract is washed with brine, dried, and concentrated to obtain the desired substances (1) 2-ethoxycarbonyl-2-methyl-b-nitro-3-oxo-4H-benz 1,oxazine, which is recrystallized from BYN (7.2 g, 6295) . "H NMR. (0M5O-46): 5 11.47 (1H, 5), 7.99 1H, aa, 3-9 Hz, 1-5 2.7 tsu, 7.85 (IN, 4, 7- 2 2.7 Hz), 7.36 (IN, y, Re 8.7 Gy), 4.23 (H, d, 22 7 Go), 1.85 (ZN, 5), 1.17 (ZN, i, ee 7.2 Gy); LCMS: purity: 98 5; MS (m/z); 281 (MH). 7.4.144 (3) b-amino-2-ethoxycarbonyl-2-methyl-3- | Solution o? Сv) 2-ethoxycarbonyl-2-methyl-b-nitro-3-oxo-4H-benzi 1,oxazine (0.5 g, 1.78 oxo-4H-benz| 1,4|oxazine mmol) in methanol hydrogenated at a pressure of 2 atm for 1 hour in the presence of 1025

ROS (0.05 g, 1025 by weight). After filtration through a pad of Celite, the solvent is removed under reduced pressure to obtain (1) b-amino-2-ethoxycarbonyl-2-methyl-3-oxo-4H.benz(! 4phoxazine. /"H NMR. "(0M850-46) ; 6 10.73 (1H, 5), 6.76 (1H, y, ze 12 Hn), 6.23. 6.20 (2H, t), 5.0 (2H, 5), 4.16 ( 28, d, 1-6.9 Hz), 1.69 (ZB. 5), 1.15 (ZN, i, 4-69 Hz); LC/MS: purity: 99 95; MS (m): 251 (MH). 7.2.145 3,5-dimethyl-4-methoxynitrobenzene To a solution of 2,6-dimethyl-4-nitrophenol (1 g, 5.9 mmol) in acetone (9 ml), potassium carbonate (1.22 g, 8.85 mmol), and then dimestyl sulfate (0.68 ml, 7. mmol).

The mixture is heated under reflux and stirred for 2 hours.

Ammonium hydroxide (1 ml) was added, and the mixture was reheated with a reflux condenser for 30 minutes. The mixture is cooled to room temperature and the solvent is removed in vacuo. The residue is poured into water, saturated with sodium chloride, and the resulting solid is filtered to obtain 3,5-dimethyl-4-He)methoxynitrobenzene. "NYAM? (РМ5О-46): 5 8.06 (2Н, 5), 3.84 (З3Н, 5), 2.42 (6Н, 8);

LC/MS: purity: 9190. 7.4.146 3,5-dimethyl-4-methoxyanilium A solution of 3,5-dimethyl-4-methoxynitrobenzene (0.83 g, 4.5 mmol) in methanol is hydrogenated under a pressure of 2 atm during And hours in the presence of 1095 РА/С (0.1 g, 1095 by weight). After filtration through a pad of Celite, the solvent is removed under reduced pressure to give 3,5-dimethyl-4-methoxyaniline. "H NMR. (0M5O-α6): 5 6.28 (2H, 5), 4.69 ( 2H,

From rgad5), 3.60 (ZN, «, 4- 0.9 Hz), 2.16 (68, 5); LC/MS: purity: 100 95. 7.4.147 142-(3-chloro-4-hydroxy-5-methylphenyl)- To a solution of 2-chloro-M4-(2,2-dimethyl-3-oxo-4H-benzi 1,4 |oxazin-6-yl)-5-fluoro-4- b»

4-Amino-2-chloro-b-methylphenol (0.146 g, benz| 1.4 oxazin-6-yl)-5-fluoro-2,4- 0.9 mmol). The mixture is heated in a hermetically sealed tube at a temperature of 00 C or pyrkmidinediamine 940358 for 24 hours. Amount received; diluted with NaO (10 ml), acidified with 2M HCl (pH 22), saturated with sodium chloride, and the resulting solid was filtered to give M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2- dimethyl-3-oxo-4H-benzyl1,4|oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine. Cleaning can be done with

By filtration through a pad of silica gel using 1-55 MeOH in (he)

SNSI", or with the help of crystallization, using the appropriate solvent system.

Alternatively, M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2-dimethyl-3-oxo-4H-benzP1,Poxazin-b-yl)-5-fluoro-2,4- pyrimidinediamine is obtained as a result of the reaction of an equimolar amount of 2-chloro-Ch4-(2,2-dimethyl-3-oxo-4H-benz| 1,4 Euxazin-3-6-yl)-5-fluoro-4-pyrimidinamine with 4- amino-2-chloro-6-methylphenol in MeOH under high pressure at a temperature of 110 "C for 24 hours or in OH with microwave heating at a temperature of 175 "C for 30-60 minutes with subsequent extraction of water. /"H NMR (0OM5O-46): 5 10.78 (IN, 5), 10.00 (1H, 5), 9.58 (IN, 5), 8.91 (1NI, 5), 8.23 (1H, 4, 12 8 g), - s 7.57 (IN, 8), 7.37 1H, 44, 2-87 g, 2-2, Gi), 7.27 (2H, t), 6 .98 IN, 4.75 8.7 Go), 2.22 (ZN, 5), 1.50 (6H, 5); LC/MS: purity: 98 95; MS (m/z): 444 (MN ). x z" 74.148 M2-(3-chloro-4-methoxy-5-methylphenyl)- Similar to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M44(2,2-dimethyl-3- oxo-schi of Ma-(2,2-limethyl-3-oxo-4H-4H-benz 1, Noxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine, M2-(3-chloro-4-methoxy -5- benz1,4oxazin-b-yl)-5-fluoro-2,4-methyphenyl)-M4-(2,2-dimethyl-3-oxo-4H-benz(14oxazineb-yl)-5-fluoro- 2,4-pyrimidinediamine K940361 pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4A-(2,2-dimethyl-3-oxo-4H-benz| 1!, Poxazin-b-yl)-5-fluoro-4-pyrimidinamine and 3-chloro-4-methoxy-5-methylaniline. /H

Yam? (0M50-4y6): 5 10.72 (IN, 5), 9.55 (1H, 5), 9.35 (TN, 5), 8.20 (IN, y, 72 4.2 Hz), 7 ,7541H, so 4, 5-24 Go), 7.46 (IN, I, 3-21 Gy), 7.36 (IN, t), 7.28 (IN, t), 7.00 (18, 4, 3-8.7 Gayu), 3.76 (ZH, 5), 2.25 (ZH, 8), 1.50 (6H, 5); LC/MS: purity: 98.99 95: MS (m/z): 458 (MN). ko 7.4.149 M4-(2,2-dimethyl-3-oxo-4H- Analogous to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2-dimethyl-3-oxo- -y 7 42) ko 60 b5 benzoxoxazin-b-yl)-5-fluoro-M2-aH-benzi 1,4 Juixazin-b-yl)-5-fluoro-2.4-pyrimidinediamine, M4-(2.2-dimethyl-3 -oxo-4H-(icdazolineb-yl)-2,4-pyrimidinediamine benz|1,Choxazin-b-yl)-5-fluoro-M2(indazolin-b-17)-2,4-pyrimidinediamine is obtained in k940363 as a result of the reaction of 2- chloro-M4-(2,2-dimethyl-3-oxo-4H-benz 1,4 oxazin-b-yl)-5-fluoro-4-trimidinamine and b-aminoindazole. NAM (рРМ50-46):5 10.71 (1Н, with), 9.64 (1Н, 5), 942

OH, 5), 8.24 (IN, 4, 1- 3.9 Gy), 8.09 (1, 5), VO CH, 5), 7.066 (IN. 4, 73-9 Gd), 7.52 an, I, 8.7 Gy), 7.37 (2H, t), 7.00 (EN, b, 1-8.7 Gy), 1.50 (6H, 5); LC/MS: purity: 96.09 95; MS (m/z): 420 (MNU. 74150 Ma-(2,2-lifluoro-3-oxo-4H- Analogous to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2, 2-dimethyl-3-oxo-benzi 1.4|oxazin-b-yl)-5-fluoro-M2-4H-benz(1,4|-oxazin-b-yl)-5-fluoro-72,4-pyrimidinediamine, M4-(2,2-difluoro-3-oxo-4H-(indazolin-b-yl)-2,4-pyrimidinediamine benz(1,4|oxazin-6b-1l)-5-fluoro-M2-(inlazoline- b-yl)-2,4-pyrimidinediamine is obtained in k940364 as a result of the reaction of 2-chloro-M4-(2,2-difluoro-3-oxo-4H-benzi 1,4|-oxazin-b-yl)-5-fluoro -4- pyrimidineamine and b-aminoindazole. "H NMR. (OM80-46): δ 12.07 (1H, 5), 9.73 (1H, c), 940 (IN, 5), 8.29 (IN , a, 12: 3.6 Hz), 8.12 (IN, 5), 8.00 (IN, 5), 7.78 (1, ad, 1-2 8.7 Hz, 22 2.4 Gu ), 7.50 (1H, 8), 7.36 (2H, t); RHLMS: purity: 94.39 59; MS (m/z): 428 (ME). 7.4151 (X) 2-chloro-M4 -(2-ethoxycarbonia-2" Reactor with a magnetic bowl, a rubber membrane and an opening for supplying Mo methyl-3-oxo-4H.-benzi and ,4|oxazin-b-yl)-. | fill (7) b -amino-2-ethoxycarbonyl-2-methyl-3-oxo-4H-benz|1,4oxazine (0.45 g, 5-fluoro-4-pyrimidine min 1.8 mmol), MeOH (4 mL), NaO (2 mL) and 2,4-dichloro-5-fluoropyrimidine (0.36 g, 2.2 mmol).

The reaction mixture is stirred at a temperature of 60 "C for 1 hour, diluted with NN (50 ml), acidified with 2M NOSI (6 ml) and treated with ultrasound. The solid substance formed is filtered off, washed with H2O and dried. Then, the crude substance is recrystallized from EMO Ds:n -hexanes for the formation of (1) 2-chloro-M4-(2-ethoxycarbonyl"2-methyl-3-oxo-4H.benz(I4)oxazin-6-yl)-5-fluoro-4-pyrimidinamine. "H NMR. (PM5O- db: 51121 (IN, 5), 10.05 018, 5), 8.39 (1M, y, 1- 3.6 Gy), 7.41-7.34 (2H, t), 7 ,13 (IN, y, 2 9hz). 8.292, 4 -7.2 Gu, 1.78 (ZN, 5), 1.17 (ZN, 6 12 7.2 Hz); LC/MS: purity: 95 95; MS (m/z): 381 (MN). 7.4.1572 (in ma-(2-ethoxycarbonyl-2-methyl-3- Analogously to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2-dimethyl-3-okovo-oxo -4H-benz(I,oxazin-6b-yl)-5-fluoro-|4H-benz(I,4|oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine, (3-) MI -(2-ethoxycarbonyl-2-

M24(3- methyl-3-oxo-4H-benzi 1,4|oxazin-b-yl)-5-fluoro-M2-(3-(methoxycarbonylmethyleneoxy)phenyl|- (methoxycarbonylmethyleneoxy)phenyl|-2,4-pyrimidinediamine are obtained as a result of the reaction of 2,4-pyrimidinediamine 2-chloro-Ma-(2-stoxycarbonyl-2-methyl-3-oxo-4H-benz 1,oxazin-6-yl)-5-fluoro-4-pyrimidinamine and Z- (Methoxycarbonylmethylethoxy)aniline 744153 5-Fluoro-M4-|2-methyl-2-(M-Mixtures M4-(2-ethoxycarbonyl-2-methyl-3-oxo-4H-benz 4 oxazin-b-yl)- 5-fluoro-M2-(3- methylaminocarbomyl)-3-oxo-4H- methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (0.069 g, 1.3 mmol), benzene I. Doxazin-b-yl|-M2-1344M- of methylamine hydrochloride (0.088 g, 1.3 mmol) and diisopropylethylamine (230 μl., 1.3 methylaminocarbonylstyleneoxyphenia!- | mmol) in MeOH (2 ml) are stirred in a beaker under high pressure at a temperature of 997°C

AND

2,A-pyrimidinedigmine KU4A0365 for 4 hours. The reaction mixture is cooled to room temperature, diluted with H2O (20 ml), the solid formed is filtered off, washed with water and dried.

The resulting residue is purified by chromatography on silica gel (CHNOCl: MeOH; 95:5 by volume) to obtain the desired 5-fluoro-M4-H2-methyl-2-(M-methylaminocarbonyl)-

Z-oxo-4H-benz|1,oxazin-6-yl|-M2-(3-(M-methylamino)carbonylmethyleneoxyphenium|-7,4- pyrimylindiamine. "H NAM? (0M5O-46): b 10.80 (1H, 5), 9.44 (IN, 5), 9.21 (IN, 8), 8.22 (1H, «o she, 88 (IN, a, 3 3.9 g), 8.06 (IN, p), 7.51-7.4 (ZH, t), 7.31 (IN, t), 7.20(1Н, 3 8.2

HO), TLI IN, 4.15 9 Hz), 5.57 (IN, 44, 1- 8.1 Hz, 3- 2.7 Hz), 4.46 (2H, 5), 2.74 (ZN , and, 154.8

Go), 2.62 (ZN, 4.3 4.8 Hz), 1.72 (ZN, 5); LC/MS: purity: 94 95; MS (m/z); 510. -oxo-benzi!.4|oxazin-b-yl)-5-fluoro-h2-041-4H-benz and 4|oxazin-b-yl)-5-fluoro-2.4-pyrimidinediamine, MA-(2,2 -dimethyl-3-oxo-4H- or methylindazolin-b-yl) 2,4 benzyl, Zoxazin-6-1l)-5-fluoro-M2-(MI -methylindazolin-b-yl) -2,4- pyrimidinediamine pyrimidinediamine K940366 is obtained as a result of the reaction of 2-chloro-MA-(2,2-dimethyl-3-oxo-4H-benzi I 4 oxazin-b-yl)-si 5-fluoro-4-pyrimidinamine and b-amino-M1 -methylindazole." nH NMR. (0M5O-ab): 6 10.74 (IN, 5), 9.48 (1H, 8), 9.42 (1H, 5), 8.24 (1H, 4, 2: 3.6 Gy), 8.16 (1H, 8), 7.94 (IN, 5y, 7.63 (IN, 4, 72

Zo 8.4 Gy), 7.46 (1H, ay, 1-84 Hz, 2: 2.4 Hz), 7.36-7.32 (2H, t), 6.99 (IN, y, 7 -9 Gy), 3.86 (ZN, (ge) 5). 1.50 (BN, 5); LC/MS: purity: 96.80 96; MO (m/z): 434 (MN). 7.4.4155 M4-(2,2-difluoro-3-oxo-4H- Similar to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2-dimethyl-3-oxo-benz) (1,4)oxazin-b-yl)-M2-(2,2-dimethyl-|4H-benzi 1,4)oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine, M4-(2 ,2-difluoro-3-oxo-"H-

C-oxo-4H-benz| 1,oxazin-b-yl)-5-benz(1,4|oxazin-b-14)-M2-(2,2-dimethyl-3-oxo-4H-benz 1,4)-oxazin-3-6 -yl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine K940367 pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-difluoro-3-oxo-4H- b-1l)-5-fluoro-4-pyrimidinamine and 6-amino-2,2-dimethyl-3-oxo-4H-benzyl,choxazine. "NYMR (0M50-46): 5 12.04 (18, 5), 10.54 (181, 5), 9.61 (IN, 5), 9.12 shsh (IN, 5), 8.17 ( IN, 4, 2- 3.6 Hz), 7.54 (1H, 49, 4-9 and, 12 2.7 Gy), 7.55 (1H, 4, 2 2.7 Hz), 7.32- s 7.26 (ZN, t), 6.87 (IN, d, 2-93 Hz), 1.46 (6Н, 5у; LC/MS: purity: 92.68 95; MS (m/z): 487 (МН. ; t 7.4156 M4A-(2,2-difluoro-3-oxo-4H- Analogous to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2-dimethyl-3- Oxo-benz 1,4-oxazin-6-yl)-5-fluoro-M24(1-4H-benz|!4-oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine, M4-(2, 2-difluoro-3-oxo-4H-methylindazolin-6-1l)-2,4-benz/1,oxazin-6-yl)-5-fluoro-M24 1-methylindazolin-b-zl)-2,4-pyrimidinediamine pyrimidinediamine 5940368 is obtained as a result of the reaction of 2-chloro-M4-(2,2-difluoro-3-oxo-4H-benz 1,4|oxazine-6-1l)-5-fluoro-4-pyrimidinamine and 6-amino-1 -methylindazole.

Go! 9.7, 5), 9.9 (IN, 85), 8.31 (IN, 4, 12: 3.9 Gy), 8.18 (IN, 5), 7.95 (IN, 5), 7.72-7.69 (IN, n), 7.65 (Н, 4.1-9 g), 7.59 (1Н, tu, 7.36 (2Н, 1, 12 8.7 Gy), 3.85 (ZN, 5); LC/MS: purity: 94.55 95; MS (m/z): 442 (MIN). ki M4-(2,2-dimethyl-3-oxo-4 NI-5 - Analogous to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2-dimethyl-3-oxo- -y (Ce) 42) co 60 b5 pyridi!4oxazin-b-yl) -M2-(3-chloro-4-4H-benzi1,4|-oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine, YM4-(2,2-dimethyl-3-oxo-4H-5 - methoxyphenyl)-5-fluoro-2,4-pyridin,4oxazin-b-yl)-M2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine pyrimidinediamine KU40371 is obtained as a result of the reaction 2-Chloro-M4-(2,2-Limethyl-3-oxo-4H-5-pyridyl-4-oxazin-6-yl)-5-fluoro-4-pyrimidinamine and 3-chloro-4-methoxyaniline. "H NMR (0M5O-46u; 5 11.20 (IN, 5), 9.39 (1H, 5), 9.34 (1H, 5), 8.221H, y, 1-33 Gy), 7.00 (IN, 5), 7.62-7.54 (2H, t), 7.47 (IN, 9, 3-8.4 Gy), 7.08 (1H, y, 1-9 Hz), 3 .87 (ZB, 5), 1.55 (6H, 5); LC/MS: purity: 97.92 95;

MS (m/zu; 445 (MN). 7.4.158 M4-(2,2-dimethyl-3-oxo-4H-5-) Similar to the preparation of 1Ch2-(3-chloro-4-hydroxy-5-methylphenyl)-M4 -(2,2-dimethyl-3-oxopyridi-1,oxazin-6b-yl)-M2-(3,5-4H-benzi 1,4|-oxazin-6b-yl)-5-fluoro-2, 4-pyrimidinediamine, M4-(2,2-dimethyl-3-oxo-4H-5-dimethoxyphenyl)-5-fluoro-2,4-pyridin,4oxazin-6-1l3-M2-(3,5-dimethoxyphenia )-5-fluoro-2,4-pyrimidinediamine is obtained in pyrimidinediamine K940372 as a result of the reaction of 2-chloro-Ma-(2,2-dimethyl-3-oxo-4H-5-pyridi 1,4 oxazin-6-yl)-5 -fluoro-4-pyrimidinamine and 3,5-dimethoxyaniline. "H NMR (OM5O-46): 5 11.15 (IN, 5), 934 (1H, 5), 9.30 (18, 5), 8, 23 (1H, 4, 1- 3.3 Hz), 7.74 (IN, ab, 2- 8.7 Hz, y: 3.9 Hz, 7.43 (IN, 4, 2- 8.7

Go), 7.02 (2H, 5), 6.16 (IN, 5), 3.75 (6H, 5), 1.53 (EN, 5); RH/MS: purity: ЮЮ 55; MS (m/z): 441 (MN. 7.444159 M243,4-dichlorophenyl)-ma-(2,2-dimethyl-3- | Similar to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4A (2,2-dimethyl-3-oxo-oxo-4H-5-pyridi I. Yaoxazin-6-1l)-5-4H-benzi 4)-oxazin-b-yl)-5-fluoro-2,4- pyrimidinediamine, 142-(3,4-dichlorophenyl)-M4-(2,2-fluoro-2,4-pyrimidinediamine K940373 dimethyl-3-oxo-4H-5-pyridi 1,4)oxazin-5-yl)-5 -fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M442,2-dimethyl-3-oxo-4H-5-pyridi 1,4 (oxazineb-yl)-5-fluoro-a pyrimidine and C 4- dichloroaniline. "H NMR (BM5O0-46); 6 11.20 (IN, 5), 9.68 (IM, 5), 9.54 (1H, 5), 8.27 (AN, a, 1- 3.6 Gy), 8.14 (IN, y, 4: 2. Go), 7.64 (IN, 49, 15: 8.7 Hz, 3-1

Hz), 7.53-7.47 (ZH, pa), 1.53 (6H, 5); LC/MS: purity: 100 95; MS (m/z): 449 (M). 7.4.160 M4-K2,2-dimethyl-3-oxo-4H.-5- Similar to the preparation of M2-(3-chloro-4-hydroxy-3-methylphenyl)-M4-(2,2-dimethyl-3-oxo - pyrido(1,oxazin-b-yl)-5-fluoro-M2-AN-benz( and Zoxazin-5-yl)-5-fluoro-2,4-pyrimilindiamine, M4-(2,2-pimethide-3 -oxoY.5-"indazolin-b-yl)-2,4-pyrimidinediamine pyrid PA |oxazin-6-yl)-5-fcor-M2-(indazolin-6-yl)-2,4-pyrimidinediamine is obtained in 2940380 as a result of the reaction of 2-chloro-M4-(2,2-dimethyl-3-oxo-4H-5-pyrido 1,4 |oxazin-b-yl)-5-fluoro-4-pyrimidinamine and b-aminoinlazole. "H NMR. (0М50-46): 511.16 (IN, 5), 9.48 (1Н, 5), 9.28 (IN, 5), 8.27 (IN, 8, 7- 3.3 Gi), 8.17 (1H, 5), 7.98 (1H, 5), 7.84 (1H, t), 7.6541H, 8, 3-9 Hn), 7.47 (1H, a, 8.7 Hz), 7.36 (1H, a, 3- 8.7 Gy), 1.53 (6H, 5); LC/MS: purity: 100 29; MS (m/z): 421 (MK 74461 M2-3-tert-butylphenyl)-Ma-(2,2- Similar to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2-dimethyl-3-oxo-dimethyl -3-oxo-4H-5-pyridinium, Х|oxazine-|4H-benz(14oxazine-6-1l)-5-fluoro-2,4-pyrimidinliamine, M2-(3-tert-butylphenyl)-M4 -(2,2-b-yl)-5-fluoro-2,4-pyrimidinediamine dimethyl-3-oxo-4H-5-pyridi I,4oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine is obtained in 8940381 as a result of the reaction of 2-chloro-M4-(2,2-dimethyl-3-oxo-4H-5-pyridi| 1,4 |oxazin-b-yl)-5-fluoro-4-

CH of pyrimidineamine and 33-ltert-butylaniline. H NMR (0M50-46U 5. 1.16 (IN, 53, 9.27 (IN, Ge t 5923 (IN, 5), 822 (EN, 4, 72 3.6 Hz), 7.74 (1 H, t), 7.70 1H, I, 1-8 g), 757 1H, 5 744 o an,a, z- 8.7 Hyd, 7.205 1H, 5 3e7.9 Gy), 7.01 (1 , а, 2 7.8 Hz), 1.53 (6Н, 5), 1.33 (9Н, 5);

LC/MS: purity: 100 95; MS (m/z): 437 (MN). 7.4162 M4-((02,2-dimethyl-3-oxo-AN-5-) | 1,4oxazin-b-yl)-35-fluoro-m2-(3-4H-benz| 1iaoxazin-6-yl)-3-fluoro-2,4-pyrimidinediamine, M4-(2,2-dimethyl- 3-oxo-4H-5-tihydroxyphenyl)-2,4-pyrimidinediamine pyrid(1,4)oxazin-6-yl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine is obtained in k940382 as a result reactions of 2-chloro-M4-(2,2-dimethyp-3-oxo-4H-5-pyridi I,oxazin-6-yl)-5-fluoro-4-(se)pyrimidinamine and 3-aminophenol. (РМ80-а6): 5 1.16 (1Н, 5), 9.29 (1Н, 5), 9.25 (IN, 8), 9.23 (IN, 5), 8.20 (1 Н, и, 1- 3.6 Hn), 7.74 (1H, y, 1- 8.4 Hz), 7.44 (1H, y, 228.7 Hz), F 723(aH, I 125 Gy), 716 Na , Re V Hn), 7.04 H, and I» 7.9 Hn), 6.40 (1H, 40, 126.9

Hz, 72 1.2 Hz), 1.53 (6H, 5); LC/MS: purity: 100 99; MS (m/z); 397 (МН. 7.4.163 Ма-4(2,2-dimethyl-3-oxo-4Н-5- Analogously to the preparation of Ч2-(3-chloro-4-hydroxy-5-methylphenyl)-М4-(2,2- pimethyl-3-oxo- -- pyridines, choxazin-6-yl)-M2-(3-fluoro-4-4H-benz(1,4-oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine, M4-(2,2-dimethyl-3-oxo-4H,5-methoxyphenyl)-5-fluoro-2,4-pyrido I, Foxazin-6-yl)- M2-(3-fluoro-4-methoxyphenyl)- 5-fluoro-2,4-pyrimidinediamine and pyrimidinediamine K940384 are obtained as a result of the reaction of 2-chloro-M4-(2,2-dimethyl-3-oxo-4H-5-pyridi I,4|oxazin-6-3Byl)u -5-fluoro-4-pyrimidinamine and 3-fluoro-4-methoxyaniline." NN NMR (0M50-46): δ 11.20 s (IN, 5), 9.42 (IN, 5), 9.35 ( 1H, 5), 8.21 (IN, y, 2- 3.5 Hyd), 7.75 (AN, y, 7- 14.4 Hy. 2-24 Hz), 7.56 (IN, 4, 1 8 Gy), 7.6 (IN, 9, 3- 8.7 Gu, 7.37 AN, 4, 7: 9.6 Gy), 7.08 (1, 75 94 Go), 3.85 ( ЗН, 5), 1.53 (6Н, 5); RI/MS: purity: 97 95; MS (m/z); 429 (МН. 7.а464 142-(3-chlorophenyl)-М4А-(2, 2-dimethyl-3- Similar to the preparation of M2-(3-chloro-4-hydroxy-3-methylphenyl)-4-(2,2-dimethyl-3-okoso-oxo-4H-5-pyridi and 4 oxazine-b- il)-5» AN-venzi I oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine, M2-(3-chlorophenyl)- M4-(2,2-" fluoro-2,4-lyrimidinediamine K940386 dimethyl-3-oxo-4H-5 -pyridi 1,4 oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-dimethyl-3-oxo-4H-5-pyridi 1,4 )oxazin-6-yl)-5-fluoro-4-pyrimidinamine and 33-chloroaniline. IN YAM" (OM50-46): 611.10 (1H, 5), 9.50 (1H, 5), 9.43 shsh (an, 5), 8.16 (IN, 4, 1- 3.3 Hz) . , gave, from 78 Hn, Z 2 Sd, 3-12 g), 143 (OH, 5); and LC/MS: purity: 100 92; MS (m/z): 415 (MH), p » 7.4.165 Ш2-(3,5-dichlorophenyl)-MA-(2,2-dimethyl-3- | M2-(3-chloro-4-) was prepared similarly tihydroxy-3-methylphenyl)-M4-(2,2-dimethyl-3-oxo-oxo-4H-5-pyridine, Choxazin-6-yl)-5-4H-benz| 1 4|oxazin-6-yl )-5-fluoro-2,4-pyrimidinediamine, M2-(3,5-dichlorophenyl)-M4-(2,2-fluoro-2,4-pyrimidinediamine K940387 dimethyl-3-oxo-4H-5-pyridi I, oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-144-(2,2-dimethyl-3-oxo-4H-5-pyridine and MPoxazin-b-yl)- 5-fluoro-4-pyrimidinamine and 3,5-dichloroaniline. N YAM? gOM50-46): 811.10 ОН, 5), 966 (1Н, 5),

Go | 9.49 (IN, 5), 8.19 (1H, t), 7.70 (2H, t), 7.39 (2H, t), 6.99 (IN, 6, 72: 1.95 P ), 1.42 (6H, 8p;

LC/MS: purity: 96 96; MS (m/z): 450 (MN). ko -y 7 42) ko 60 b5

7.4.166 74-(2,2-dimethynyal-3-oxo-4H-5- Similar to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2-limethyl-3-oxo) - pyridinium 1,4Hyoxazin-6-1l)-5-fluoro-M2-(1-AN-benzyl1,4oxazin-b-yl)-5-fluoro-2,4-pyrimidinidiamine, M4-(2,2-dimethyl -3-oxo-4H-5- methylindazolin-b-yl) "2,4- pyridi 4 oxazin-6-yn)-5-fluoro-M2-(1-methylinlazolin-6-yl)-2,4-pyrimidinediamine pyrimidinediamine K940359 is obtained as a result of the reaction of 2-chloro-M4-2,2-dimethyl-3-oxo-4H-5-pyride| 1,oxazin-6-yl)-5-fluoro-4-pyrimidinamine and b-amino-I-methylindazole. /"H NMR (OMI5O-46): 5 11.22 "IN, 5), 9.60 (IN, 5), 9.43 (IN, 5), 8.29 (1H, y, 72 3.6 Hz), 8.13 (1, 5), 7.95 (1H, 5), 7.72 (1H, d, 128.4 Hz), 7.64 (1H, y, 7-9 Hz, 7, 47 (IN, y, 7- 8.1 Hz), 7.34 (IN, ab, 3- 8.7 Hz, 32 1.8 Hn), 3.19 (ЗН, 5), 1.53 (6Н , 5); EX/MS: purity: 100 90; MS (m/z): 235 (MN). 7.4.167 142-(3-chloro-4-trifluoromethoxyphenyl)-Ma4- | Similar to the preparation of M2-(3- chloro-4-hydroxy-5-methylphenyl)-niM4-(2,2-dimethyl-3-oxo-(2,2-dimethyl-3-oxo-4H-5-AN-benz|14)oxazineben»eyl) -5-fluoro-2,4-pyrimidinediamine, M2-|3-chloro-4-pyridi 1.oxazin-b-yl)-5-fluoro-2,4-trifluoromethoxyphenyl|-M4-(2,2-dimethyl- 3-oxo-4H-5-pyridi 1.oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine KO40390 pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-dimethyl-3-oxo- 4H-5-pyridinium 1,4oxazin-b-yl)-5-fluoro-4-pyrimidinamine and 3-chloro-4-trifluoromethoxyaniline. "H 70 NMR (OM5O-i6 8 11.24 (IN, 5), 9.16 (IN, 5), 9.60 (IN, z), BB (IN, 4, Z: 3.6 Go), 8.14 (IN, 44-24 Hz), 7.70 (IN, 9Cha, 35 9 С , i- 2.7 tsu, 7.54-7.43 (ZN, t), 1.53 (6H, 5); RHUMS: purity: 94.6 55; MS (m/z): 499 (MN). 7.4.168 Mm2-(3-chloro-4-methoxy-5-methylphenyl)- Similar to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2-dimethyl-3-oxo- 14442,2-dimethyl-3-oxo-4H»4H-benz(i,oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine, IM2-4(3-chloro-4-methoxy-5-pyridinium 4 (oxazin-6-yl)-5-fluoro-2,4-methylphenyl)-M4-2,2-dimethyl-3-oxo-4-5-pyridine (1,oxazin-6-1)-5-fluoro -2,4- pyrimidinediamine 2940391 pyrimidinediamine is obtained as a result of the reaction of 2-chloro-44-(2,2-dimethyl-3-oxo-4H-5-

And pyridi1,oxazin-b-yl)-5-fluoro-4-pyrimidinamine and 33-chloro-4-methoxy-5-methylankyline. "I

NMR (pM50-a6): 511.20 (1H, 5), 9.24 (1H, 5), 9.40 (1H, 5), 8.23 (1H, 49, 3- 3.3 Hz, 3 - 09

Ti), 7.76 (1H, a, 2: 2.7 7), 7.61 TA, 4, 2- 8.4 Hz), 7.47 (1H, 8.38, Gi), 742 (1H , and, 2 7

Hz), 3.76 (ZN, 4, 25 1.2 Gy), 2.27 (ZA, 5), 1.53 (6H, 5; LC/MS: purity: 100 95; MS (m/z) : 459 (МН). 7.4169 M442,2-dimethyl-3-oxo-4H-5- Similar to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2-dimethyl-3- oxopyridi1,oxazin-b-yl)-5-fluoro-M2-(3-4H-benzyl1,4)oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine, 144-(2,2- dimethyl-3-oxo-4H-5-methoxycarbonylmethyleneoxyphenyl)-2,4- | pyridine I, oxazine-b-1l)5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenyl-2,4-pyrimidinediamine K940392 pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M442,2-dimethyl-3-oxo-4H-5- ythiridi 1,4-oxazin-b-yl)-5-fluoro-4-pyrimidinamine and 3-(methoxycarbonylmethyleneoxy)anilic. IN NMR (rm5o0-46): 511.16 (IN, 5), 9.36 (IN, 5), 9.34 (1Н, 5), 8.231, 4, 2- 3.3С), 7.69 (IN, y, 1 8.7 Hz), 7.47 14, 9, 3- 8.7 Gy), 7.82 (IN, 5), 737 Na, with 8 GI), 717 (1, ze B ). 5); LC/MS: purity: 94.69 90; MC (m/l): 469 (MN. 14170) Analogously to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-Ch4-(2,2-dimethyl-3-oxo-

Ma43,4-ethylenedioxyphenyl)-5-fluoro-2,4- | 4H-benz 1,4)oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine, M2-(3-chloro-4-hydroxy-5" o pyrimidinediamine 8940393 methyphenyl)-m4-(3,4- stylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 7"xpor-Ma-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 4-amipo-2-chloro-b6-methypphenol. IN YAM (rm50-avu: 5 9.19 (IN, a, 1: 3.5 Go), 9.05 (18, 5), 8.А(IN, 5810 (1, y, 7 3.9 Hz ), 7.62 (IN, 4, 12 2.7 Hzu, 7.36 (1Н, 4, 22 1.8 Hz), 7.31 (ВН, t), 7.27 (IN, d,1- :2.7 Hz), 6.871, 4, 1-5 8.4 Hz), 4.31 (AN, 5), 2.22 (ZN, 8); LC/MS: (Te) purity: 96.9890 ; MS (m/z): 403 (MN). 74471 M2-(3-chloro-4-hydroxy-5-methylphenyl)- Similar to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4- (2,2-dimethyl-3-oxo-He»)

M442,2-dimethyl-3-oxo-4H-5-4H-benzi 1,4|oxazine-b-1l)-5-fluoro-2,4-pyrimidinedigmine, M2-(3-chloro-4-hydroxy-5 - pyridi 1,4|oxazin-b-yl)-5-fluoro-2,4-methylphenyl)- M4-(2,2-dimekyl-3-oxo-4H-5-pyrid| i,4|)oxazin- 6-1l)-5-fluoro-2,4-pyrimidinediamine 2940394 pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(2,2-dimethyl-3-oxo-4H-5- or pyridinium and oxazin-b-yl )-5-fluoro-4-pyrimidinamine and 4-amino-2-chloro-b-methylphenol, /Н

NMR (0M50-y6): 511.16 (IN, 5), 9.27 (IN, 5), 9.15 (IN, 5), 8.67 (1H, 5), 8.19 (IN, d , 2-3.6 urine

Sy), 7.64 (2H, t), 7.42 (1 H, d, 1-8.4 Hn), 7.29 (1, 4, 1- 2.7 Hz), 7.22 (ZH, 5 ), 1.53 (6H, 5);

LC/MS: purity: 97.6990; MS (m/z): 444 (M. and c 7.4172 M2-(3,5-dimetnya-4-methoxyphenyl)-M4- Analogously to the preparation of M2-(3-chloro-4-hydroxy-5-methyyaphenyl)- M44( 2,2-dimethyl-3-OXO-(2,2-dimethyl-3-oxo-4H»5»4H-benzi 1,4 uxazin-6b-yl)-5-fluoro-2,4-pyrimidinediamine, M24( 3,5-dimethyl-4-methoxyphenyl)-pyridi 1,oxazin-6-yl)-5-fluoro-2,4- 144-(2,2-dimethyl-3-oxo-4H-5-pyride) 1.4 | oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine pyrimidinediamine K940395 is obtained as a result of the reaction of 2-chloro-M442,2-dimethyl-3-oxo-4 A. 5-pyryl 1, CHoxazin-6-yl) -5-fluoro-4-pyrimidinamine and 3,5-dimethyl-4-methoxyaniline. "NN NMR (0M50-96:

B1116(Н, 5), 9.23 (IN, 5), 9.11 (IN, 5), 8.19 (IN, 4, 12 3.6 Hz), 7.69 (IN, d, 1 8 ,1 Gy), 7.44 "

Н,д, 12 8.4 Hz), 7.33 (2Н, 5), 3.68 (ЗН, 5), 2.23 (ОН, 5), 1.53 (ЕН, 5); RHLMS: purity: 9995;

MS (m/z): 439 (Mn. in s 7.4173 M2-(3,5-dimethyl-4-methoxyphenyl)-Ma- Analogously to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4- (2,2-dimethyl-3-oxo-(3,4-styrenedioxyphenyl)-5-fluoro-2,4-4H-benz(i,oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine, 142-(3,5-dimethyl-4-methoxyphenyl)-p pyrimidinedismin K940396 Mma-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2- and R. chlor-M4-( 3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3,5-dimethyl-4-methoxyaniline. "H NMR (DM85O-46): δ 10.06 (IN, 5), 9.85 (IN, 5), 8.25 (18, d, 12 4.8 Gy), 7.33 IN, 4, 1-24 Hz), 7.24 (2H, 5), 7.29 (IN, 4, 7-27 Hz ), 6.91 (IN, d, 3-8.4 Gy), 4.32 (48, 5), 3.71 (ZH, 5), 2.25 (6H, 5); LC/MS: purity : 96.69; MS (m/z): 397 (MN). 74474 142-(3-chloro-4-methoxy-5-methylphenyl)- Similar to the preparation of M2-(3-chloro-4-hydroxy-5-methylphenium) )-M4-(2,2-dimethyl-3-oxo-(ee) M443,4-ethylenedioxyphenyl)-5-fluoro-2,4- | 4H-benzi 1,4 oxazine-6-1l)-5-fluoro -2 4-pyrimidinediamine, M2-(3-chloro-4-methoxy-5-pyrimidinediamine KU40 397 methylphenyl)-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-MA-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine and 3-chloro- and 5-methyl-4-methoxyaniline. "H NMR (0OM5O-46)3: 5 9.88 (211, bgoady 5), 8.26 (1H, 6, 7: 4.2 -y (Ce) 42) ko 60 b5

Go), 7.64 (IN, 5), 741 (IN, 5), 7.30-7.28 (IN, t), 7.25-7.20 (IN, t), 6.92 (IN, b , 7- 190.2 Hz), 4.32 (AN, 5), 3.79 (ZN, 5), 2.29 (ZN, 5); LC/MS: purity: 94.8195; MS (m/z: 417 (MN). 7.4.175 5-fluoro-M2-I340M- Solution M4-(3-carboxy-4-trifluoromethoxyphenyl)-5-fluoro-M2-/3-(M- methylamino)carbonylmethyleneoxyphenial |- | methylamino)carbonylmethyleneoxyphenes of 1)-2,4-pyrimidinediamine in DMF are treated by RuVgoR

MA-434(M-morpholino)carbonyl-4-(bromo-tris-pyrrolidine-phosphonium-hexafluorophosphate) and morpholine. The mixture is stirred with 9 trifluoromethoxyphenyl|-2,4- for 1 hour at a temperature of 22 C and purified by methanol flash chromatography on pyrimidinediamine (K950411) silica gel to form 5-fluoro-M2-(340M-methylamino)carbonylmethyleneoxyphenyl|-M4-|3 - (M-morpholino)carbonyl-4-trifluoromethoxyphenyl|-2,4-pyrimidinediamine in the form of a white solid. YIN YAM? (0M50-a6): 5 9.62 (5, IN), 9.29 (5, 1H), 7.77-8.17 (t, 7H), 7.12 (IN, Is 8.1 Gy) , 6.48 (t, 1H), 4.36 (5, 2H)), 3.02-4.36 (ta, 8H), 2.64 (5, ЗН); LC/MS: purity: 92.99; MS (m/z): 565.34 (MN). 744176 ma-13-(M-2-aminoethylamico)carbonyl-3- | Solution of M4-(3-carboxy-4-trifluoromethoxyphenyl)-5-fluoro-M2-Y3-(M-710 trifluoromethoxyphenyl)-5-fluoro-M2-(3-(0M4-|methylamico)carbonylmethyleneoxyphenyl|-2.4- pyrimidinediamine in DMF is treated with methylamino)carbonylmethyleneoxyphenyl-|RuBhor and 1,2-diaminooctane. The mixture is stirred for 1 hour at a temperature of 2,4-pyrimidinedismine (K950406) 22.7C and purified by flash chromatography on silica gel to form M4-|3 -(0M-2-aminoethylamino)carbonyl-3-trifluoromethoxyphenyl-5-fluoro-M2-134(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in the form of a white solid, LC/MS: purity: 10095; MS ( m/z): 538.5 (MH). 74177 5-fluoro-M4-13-(M-methylamino)carbonyl- | Solution MA-(3-carboxy-4-trifluoromethoxyphenyl)-5-fluoro-M2-I34( M-4-trifluoromethoxyphenyl)-142-(3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in DMF is treated with methylamino)carbonylmethyleneoxyphenyl|-|RUVTOR and M-methylamine. The mixture is stirred for 1 hour at a temperature of 22 2,A-pyrimidinediamine (K950407) "S and purified by flash chromatography on silica gel to produce 5-fluoro-M4-13-(M-methylamino)carbonyl-4-trifluoromethoxyphenyl-Mch2-(3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in the form of a white solid matter. LC/MS: purity: 93.395; MS (m/z): 496.27 (M.N. 7.4.178 5-fluoro-M44(3-IR42-4(M- Solvent M4-(3-carboxy-4-trifluoromethoxyphenyl)-5-fluoro-х2- 13-(M-methylamino)styreneamino)carbonyl-4-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in DMF is treated with trifluoromethoxyphenyl|-M2-Y3-(M-RubgoR and M1-methylamino-2-aminohethane). I hours at a temperature of 22 "C and purified by flash chromatography on silica gel to form 2,4-pyrimidinediamine (KU50408) 5-fluoro-M4-(3-P442-(M-methylamino)styreneamino)carbonyl -4-trifluoromethoxyphenyl|-M2-|3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine as a white solid LC/MS: purity: 81.695 MS (m/z): 552.37 (MH) 74479. 4-pyrimidinediamine in DMF is processed sem

MA-I3-(M-piperidinnocarbonyl-4- | RuVgoR tapiperidine. The mixture is stirred for 1 hour at a temperature of 22 C trifluoromethoxyphenyl)-2,4- and purified by flash chromatography on silica gel to form 5-fluoro-M2-I3- 40M- o pyrimidinediamine (K950409) methylamino)carbonylmethyleneoxyphenyl|-Mm4-|3-(M-tiperidinocarbonyl-4-trifluoromethoxyphenyl)|-2,4-pyrimidinediamine in the form of a white solid. LC/MS: purity: 90.495; MS (m/z); 563.36 (MN). 7.4.180 (А-М44341М1,2- Solution M4-(3-carboxy-4-trifluoromethoxyphenyl)-5-fluoro-М2-134(М» dihydroxypropylamino)carbonyl-4-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine in DMF treated with RubgorR (Ce) trifluoromethoxyphenyl|-5-fluoro-х2-(3-(M- | and (K)-1,2-dihydroxypropylamine. The mixture is stirred for 1 hour at methylamino)carbonylmethyleneoxyphenyl|- | a temperature of 22 "С and purified by flash chromatography on silica gel to form (e") 2,4-pyrimidinediamine (KU50410) (vu ma-(3-19-(1,2-dihydroxygurylamino)carbonyl-4-trifluoromethoxyphenyl|-5-fluoro-M2-|3 - (M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in the form of a white solid substance. LC/MS: purity: 82.69; MS (m/z): 569.34 (My. h 7.ALVI (3 4 -(M-tert-butoxycarbonyl)amino-b- | A solution of (i) 4-amino-b-nitro-1-benzopyran in dioxane-water is treated with di-tert-mitro-1-benzopyran with butyl carbonate and sodium bicarbonate. The mixture is stirred for 2 hours at a temperature of 0 "C and diluted with hexane. The mixture was filtered and the solid residue is carefully washed with hexane and dried under reduced pressure to give (e) 4-(h-c tert-butoxycarbonyl)amino-b-nitro-1-benzopyran as a pale yellow solid. "H NMR (SOSIv): 6 8.23 (y, 1H, 2-27 Hz), 8.04 (ai, 1H, 4- 2.7, 9.6 Hyd), 6.88 (4, 1H, 12:9.6 Hp), 4.89 (p5, 1H), 4.81 (B5, 1), 4.26-4.38 (p 2H), 2.03-2.26 (t, 2H) 7.4182 (9 MA-1A4 (M-tert- Mixture CE) 440M-tert-butoxycarbonyl)amino-b-nitro-I-benzopyran and RAS (1029) in MEON butoxycarbonyl)amino-I -benzopyran-b- are hydrogenated at temperature 22 "C for 3 hours (pressure 2.7 atm). The mixture of yl)y-2-chloro-5-fluoro-2,4-pyrimidinamine is filtered and concentrated to dryness to obtain b-amino-4-(M-tert-butoxycarbonyl)amino-1-benzopyran as a brown oil . The resulting b-amino-4-(M-tert-butoxycarbonyl)amino-1-benzopyran oil is reacted with 2,4-dichloro-5-fluoro-pyrimiline in MeOH at a temperature of 70 C for 2 hours. The reaction mixture is diluted with water, and the formed precipitate is filtered to obtain (5) M4-14-4(M- and tert-butoxycarbonyl)amino-1-benzopyran-b-yl)-2-chloro-5-fluoro-2,4- pyrimidineamine in the form of a pale yellow solid. "H NMR (0М50-46); 5 9.85 (5, IN), 8.22 (d, 1Н,1- 2.4 g), 7.38 (t, ЗН), 6.75 (0, 1H, 1: 9.6 Hz), 4.15-4.72 (t, ЗН), 1.88-2.01 (st, 2H)), 1.42 (5,

ZNU; LC/MS: purity; 92.39; MS (m/z): 397.02 (MN). 7.4.183 (53 m4414-(M-tert» Equimolar solution of (2) M4-I144(M-tert-butoxycarbonyl)amino-1-benzopyran-6-butoxycarbonyl)amino-1-benzopyran-b-yl)-2 -chloro-5-fluoro-2,4-pyrimidinamine and 3-(4-methylamino)carbonylmethyleneoxyaniline in (ee)yl)-5-fluoro-M2-134(M-MeOH) is heated in a hermetically sealed tube at a temperature of 110 "C for 24 methylamino)carbonylmethineoxyphenyl|- | hours. The resulting reaction mixture is diluted with water, and the solid substance is removed from 2,4-pyrimidinediamine (K950405) by filtration, obtaining (1-) M4-(4-(M-tert-butoxycarbonyl)amino- |-benzopyran- and b-yl)-5-fluoro-IIM2-(3-(M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine in the form of a white solid. "H NMR (0M50-96): 6 9.24 (in, IN), 9.04 (5, 1H), 8.01 (y,

IN, 1-24 Hz), 7.93 (4, IN, 154.5 Gy), 7.60 (y, 1H, 1-72 Gy), 7.22-7.36 (t, ZN), 7 .07 (B IN, 1-84 Go), 6.69 (y, IN, 22 9.0 Go), 6.56 (pz, NI), 4.70 (t, 1H), 4.29 (5 , 2H), 4.17 (t, 2H), 2.64 (5, ЗН)), 1.88-2.08 (t, 2H), 1.40 (v, 9H); RHLIS: purity: 93.75; MS (m/zu: 537.28 (MM. 7alva (33 44(M-tert-butoxycarbonyl-Mi- A solution of 4-amino-b-nitro-I-benzopyran in THF is treated with chthrium hydride, and then methyl)amino-b -nitro-1-benzopyran with methyl iodide.The mixture is stirred for 24 hours at a temperature of 0 C.

The mixture is diluted with water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure to obtain (1) 4-(Mi-tert-butoxycarbonyl-M-methyl)amino-b-nitro-1-bsnzopyran as a pale yellow solid, "H NMR (SOS ): 5 7.98 (44, 1H, 72 3.4, 9.3 Hz), 7.90 (b5, 1H), 6.82 (4, IN, 72:9.3

Ty), 5.65 (B5, 1NU, 4.18-4.44 (t, 2H), 1.98-2.06 (t, 2), 2.55 (5, ZN). 7.4.185 ( 33 ma-14-(M-tert-butoxycarbonyl-M- Mixture (3) 4-(M-tert-butoxycarbonyl-M-methylamino-b-nitro-1-benzopyran and PO/C (1095) methyl)amino-I -benzopyran-b-yl|-2-chloro- | in MeOH is hydrogenated at a temperature of 22 "C for 3 hours (pressure 2.7 atm). The 5-fluoro-2,4-pyrimidinamine mixture is filtered and concentrated to dryness, obtaining b-amino-44M-tert-butoxycarbonyl-Mi-methyl)amino-I-benzopyran in the form of a brown oil. Conduct the reaction of the obtained Ce) b6-amino-4-(M.tert-butoxycarbonyl-M-methyl)amino-I "-benzopyran with 2,4-dichloro-5-fluoro-pyrimidine in MeOK at a temperature of 70 "C for ? hours.

The mixture is diluted with water, and the precipitate formed is filtered to obtain (3) M4-(4-(M-tert-butoxycarbonyl-M-methyl)amino-I-benzopyran-b-yl|-2-chloro-5-fluoro-2, 4-pyrimidinamine in the form of a pale yellow solid. LC/MIS: purity: 88.05; MS (ma): 408.14 (M. 7.4.186 (33 5-fluoro-M4-(44(M-methyl)amino -1- Equimolar solution of (5) M4A-14-(M-tert-butoxycarbonyl-M-methyl)amino-1-benzoniran-b-yl|-M2-I3-(0m-benzopyran-b-yl|-2 -chloro-5-fluoro-2,4-pyrimidinamine and 34(M- methylamino)carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyaniline in MEON is heated in a hermetically closed 2,4-pyrimidinediamine (K950412) tube in the presence of a catalytic amount of trifluoroacetic acid at a temperature of 110 "C for 24 hours. The reaction mixture is diluted with water, the solid substance is isolated by filtration to obtain (3) 5-fluoro-M4-|(4-M-methyl)amino-1-benzopyran-b-yl|-M2-I34 (M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine. "H NMR (rm50-v6): δ 9.62 (5, 1H), 9.46 (5, 1H), 8.71 (B5, ZNI), 8.01-8.12 (t Z), 7.47 (v, IN), 7.39 (t, 19), 7.27 (a, 1H, 7-72 Hz), 7.11 (0 1H, 157.2 Gy), 6.86 (4.1, 3 7.0 Gv), 6.46 (t, 1), 4.20-4.46 (t, ZNU 31 ( 5, ZN), 2.64 (0, ZN. 1-2 4.8 Hu, 2.55 (in, ZN), 2.05-2.19 (t, 2H); LC/MS: purity: 94.825; MS (m/z): 451.17 (M). 7.4.187 (3) ma-444(M-tert-butoxycarbonyl-M-Ozchin of an equimolar amount (g) Ma4-14-(M-tert-butoxycarbonyl-M-methyl)aminog1» methylamino-I«benzopyran-b-yl -5-fluoro-|benzopyran-b-yl|-2-chloro-5-fluoro-2,4-pyrimidinamine and 34(M-

Ш М2-13-(09- methylamino)carboxylmethyleneoxyaniline in MEOH is heated in a hermetically sealed sem that methylaminocarbonylmethyleneoxyphenyl|- | tube at a temperature of 80 "C for 7 days. As a result of water treatment, we get 11-5-fluoro-M2-|3-0M-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamic in the appearance of a white solid. "H NMR (0M50-j6); 6 10.22-10.34 (t, ZNO), 8.23 (4, 1Н, 12 5.1 Hz), 7.09 (4, IN, 1-4.2 Hz), 6.98-7 ... 18 (b5, 1H), 4.15-4.36 (t, 5H), 2.63 (5, ЗН), 1.90-2.20 (t, 2H), 1.44 (5, 9H) ; R/MS: purity: 97.395; MS (m/z): 551.25 (M). (Che) 7.4.188 (3) 44(M-acetyl)amino-b-nitro-1- A solution of 4-hydroxy-6-niro-1-benzopyran in dry acetonitrile is treated with concentrated sulfuric acid. The mixture is stirred for 1 hour at a temperature of 22 °C to obtain (5) 4-(M-acetyl)amino-6-nitro-1-benzopyran in the form of a pale brown precipitate, which is filtered off and dried. SUSIz): 6 8.13 (4,

IN, 2- 2.8 Ga), 8.04 (44, 1 H, 5- 2.8, 8.7 Gyu), 6.88 (4, 1H, He 8.7 Hz), 5.87 ( B5, 1H), 5.17-5.24 h- (t, 1H), 4.25-4.39 (t, 2H), 2.04-2.26 (t, ?H), 2.08 (5, ZN). 7.4.189 (73 4-amino-b-nitro-1-benzopyran A solution (t) of 44(M-acetyl)amino-b-nitro-1-benzopyran in concentrated HCl is heated with a reflux condenser for 16 hours. The reaction mixture is concentrated to a dry state under reduced pressure and transferred to an alkaline solution by adding potassium carbonate. (ee)

Water is added, and the aqueous phase is extracted with methylene chloride, dried over magnesium sulfate. As a result of removal of volatile substances under reduced pressure, (g) 4-amino-b-nitro-1-benzopyran is obtained as a yellow solid, which is used in subsequent operations without additional purification. /"H YAM (SOS): 5 8.23 (d, 1H, i 3.0 t), 7.95 (ad, 1H, ih 3.0, 950 Gu), 6.80 (4, GE, 1 -2 9.0 g), 2.04-4.41 (t, ZNU, 1.78-2.14 (iv, « 2). 7.4.190 (5)-4-amino-b-nitro-I-benzopyran (1 )- The solution of (C)-4-amino-6-nitra-1-benzopyran in stanol-water is treated with (1)-tartaric acid from ()-tartaric acid with hydrochloric acid and heated to form a pure solution. The mixture is stored for three days at a temperature of 22 °C, and the precipitate formed is filtered off and carefully washed with ethanol to retain enantiomerically pure (5)-4-amino-6-nitrobenzo-1-pyran (0)-CH)-

H NMR of tartaric acid salt. H NMR (OM 50-46): δ 8.44 (4, 1Н, 3 2.7 Hz), 8.08 (44, 1Н, and » 1-2Л1,9,3 Hz), 7.01 (a, 1H,4- 9.3 Go), 4.32-4.39 (t, ZH), 3.97 (5, 2H), 1.90-2.26 (t , 2H). 7ALO (K)-4-amino-b-nitro-1-benzopyran (0)4- | A solution of (7)-4-amino-b-nitrobenzopyran in stanol-water is treated with 0-(-)-tartaric acid and hydrochloric acid and heated to form a pure solution. The sums are stored for 3 days at a temperature of 22 °C, and the formed precipitate is filtered off and carefully washed with ethanol to obtain enantiomerically pure (K)-4-amino-b-nitro-I"benzopyran (13)4(-)- so vinnokam" acid salt. "H NMR (OM5O-4c): δ 8.44 (y, 1H, 2: 2.7 Hz), 8.08 (44, IN, 1-2.7, 9.3 Hz), 7.01 ( 4, 1H, 1-9.3 Rad, 3.32-4.39 (tp, ZNU, 3.97 (5, ZNU, 1.90-2.26 (t, 78). ko t -y 7 42 ) ko 60 b5

7.4.1192 (5)-M4-|4-4(M-benzyloxycarbonyl)amino- | A solution of (5)-4-amino-6b-nitro-I-benzopyran in dioxane is treated with 1-benzopyran-5-yl|i-2-chloro-5-fluoro-4-benzylchloroformate and sodium bicarbonate. The sums are stirred for 1 hour with pyrimidineamine (8950413) at a temperature of 0 C and diluted with hexane. The mixture was filtered, and the solid residue was carefully washed with hexane and dried under reduced vacuum to give (5)-4-(M-benzyloxycarbonyl)amino-b-nitro-1-benzeneirane as a pale yellow solid. The crude substance is dissolved in EN and treated with iron powder and ammonium chloride. The mixture is stirred for 2 hours at a temperature of 85 C and filtered to form a pure solution, which is diluted with water. The aqueous phase is extracted with dichloromethane, the organic phase is dried over magnesium sulfate. As a result of removal of volatile substances under reduced pressure, (5)-6-amino-44(M-benzyloxycarbonyl)amino-!-benzopyran is obtained in the form of a brown oil. As a result of the reaction of (5)-6-amino-4-0M-benzyloxycarbonyl)amino-I-benzopyran and 2,4-dichloro-5-fluoropyrimidine in MEOH for 2 hours at a temperature of 70 "C with a standard dilution with water and filtration of the formed of the residue, (5)-2-chloro-M4-4-4(M-benzyloxycarbonyl)amino-1-benzopyran-6b-1l)-5-fluoro-4-ivrimidineamine is obtained as a pale yellow solid. -46): 5 9.87 (5, 18), 9.23 (8, IN, 7- 2.4 G i), 7.85 (41.49 g), 7.25-7.45 (t , 7H), 6.77 (4, 18, 2-8.4 Hz), 5.08 (5, 7H), 4.75 (b5, 1H), 4.19 (5, 2H), 1.93 -2.06 (t, 7NU; LC/MS: purity: 97.29; MS (m/z): 429.4 (MH). 7.4.193 (K)k2-chloro-M4-(4-(М - A solution of (K)-4-amino-b-nitro-I-benzopyran in dioxane-water is treated with benzyloxycarbonyl)amino-1-benzopyran-, benzyl chloride and sodium bicarbonate. The mixture is stirred continuously and b-il)|-5 -fluoro-4-pyrimidinamine (8950413) | hours at a temperature of 0 "C and diluted with hexane. The sums are filtered, and the formed solid is carefully washed with hexane and dried under pressure to obtain (K)-44(M-benzyloxycarbonyl)amino-b-nitro-I-benzopyran in the form of a pale yellow solid. The raw substance is dissolved in RON and treated with iron powder and ammonium chloride. The mixture is stirred continuously at 85 "C and filtered to obtain a pure solution, which is diluted with water. The aqueous phase is extracted with dichloromethane and the organic phase is triturated over magnesium sulfate. Volatile substances are removed under reduced pressure to obtain (K.)-b-amino-4- 40M4-benzyloxycarbonylzamino-!-benzopyran in the form of a brown oil. As a result of the reaction of (K)-6b-amino-44M-benzyloxycarbonyl)amino-1-benzopyran and 2,4-dichloro-5-fluoropyrimidine in MeOH for 2 hours at 70 "C followed by dilution with water and filtration of the resulting residue gives (K)-2-chloro-M4-(440M4-benzyloxycarbonyl)amino-I-benzopyran-b-yl|-5-fluoro-4-pyrimidinamine in the form of a pale yellow solid . /H NMR (YUM 80-46): 5 9.87 (5, 183, 9.23 (4, 1H, 7- 2.4 Hn), 7.85 (y, IN, 7-90 Gy), 7 ,25-7.45 (t, 72), 6.77 (y, IN, 2-8.4 Gy), 5.08 (5, 2H)), 4.78 (B5, 18), 4.19 (8, 29), 1.93-2.06 (t, 2NU, RH/MS: purity: 96.195; MS (m/z): 429.4 (MN). 74194 (5)-m4-14-(M-benzeneoxycarbonyl)amino-|(5)-2-chloro-M4-|4-(M-benzyloxycarbonyl)amino-1-benzopyran-b-yl )-5-fluoro-4-1-benzopyran-6-yl)|-5-fluoro-M2-I34M-pyrimidinamine and an equimolar amount of 3-(M-methylamino)carbonylmethyleneoxyaniline Ge) methylamino)carbonylmethyleneoxyphenia|)- | dissolved in MeOH and heated in a sealed tube at 11072 for 24 2,A-pyrimidinediamine (K950417) hours. As a result of aqueous treatment, (5)-M4-14-(M-benzyloxycarbonyl)amino-1-benzopyran-b-yl|-5-fluoro-im2»|34(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine is obtained in in the form of a white solid. Н NMR (0M80-45): 5 9.83 (f5, IN), 9.58 (065, 1), 8.12 (b, IN, 3-5 2.4 Go), 7.94 (t, 1NU , 7.80 (9, IN, I- 8.7 Hz), 7.56 (t, 18), 7.1- 7.36 (t, NI), 6.72 (4, 1H, 3: 8.7 Gi), 6.56 (t, IN), 5.04 (ta, 2H)), 4.79 (t, IN), 4.17-4.30 (t, (se) 4H), 2.63 (5, ZNU, 1.91-2.08 (t, 7NU; PH/MS: purity: 93.690; MS (m/z): 571.26 (M). 7.4.195 ()-М4-14-( M-benzyloxycarbonyl)amino-|(K)-2-chloro-M4-14-(M-benzyloxycarbonyl)amino-1-benzopyran-6-yl)-5-fluoro-4-b»1-benzopyran-b-yl |-5-fluoro-M2-(3-4M-pyrimidinamine and an equimolar amount of 3-(M-methylamino)carbonylmethyphenoxyaniline methylamino)carbonylmethyleneoxyphenyl|- | are dissolved in MeOnH and heated in a hermetically closed tube at 110 "C for 2 h. ,4-pyrimidinediamic (5950418) 24 branches. As a result of aqueous treatment, (K)-M4-(440h- benzyloxycarbonyl)amino-I-benzopyran-b-yl|-5-fluoro-M2-| 3-0» methylamino) carbonylmethyleneoxyphenyl)-2,4-tyrimidinediamine in the form of a white solid substance. "H NMR (0M5O0-a6): 5 9.83 (B5, 1H), 9.58 (5, 1), 8.128, 111, 22 2.4 Hz), 7.94 (t, 18), 7.80 (4, 1H, 1-8.7 Go), 7.56 (t, 185), 7.11-7.36 (t, ZNU), 6.72 (8, 1H, and: 8.7 tsu, 6.56 s (t, 180), 5.04 (t, 2H)), 4.79 (t, IN). 4.17-4.30 (t, 4H), 2.63 (5, ЗН), 1.91-2.08 (t, 28);

LC/MS: purity: 92.595; MS (m/z): 571.26 (MK). 7.4.196 (5)-Ma-(4-amino-1-benzopyran-6-yl)-5-(8)-M44-14-(M-benzyloxycarbonyl)amino- and -benzopyran-6-1l|-5 -fluoro-M2-I34(0M- fluoro-Mm2-I3-0M- methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine and Ra/C 1095 (5095 content of methylamino)carbonylmethyleneoxyphenyl|- | oxen) are suspended in MeOH and hydrogenated in a Parr apparatus for 14 hours (22 2C, "2.4-pyrimidinediamine (K950420) pressure 2.7 atm). The suspension is filtered through celite and washed with MeOH.

The combined filtrates are concentrated under reduced pressure to obtain (5)-М4-(4-amino-1-benzopyran-b-yl)-5-fluoro-М12-/3-0М-methylamino)carbonylmethyleneoxyphenyl|-2,4- - с pyrimidinediamine as a white solid. "H NMR (0M50-46): 6 9.60 (in, IN), 9.46 (5, IN), 8.73 (B5, ЗН), 8.00-8.10 (t, Z), 7.47 (5, 1), 7.42 (t, IN), 7.29 (0, 1H, 357.2

GU Gi, 7 (BI, I 7.2 g), 6.824, 18, 177.0 Hz), 6.45 (t, 1 NI), 4.23-4.46 (t, ZNI), 4.31 (5, i t Z), 2.63 (0, ЗН, 2-4.8 Hz), 2.09-2.29 (t, 2Н); LC/MS: purity: 98190; MS (m/zu: 437.20 (MU. 7.4197 (BA Ma4(4-amino-1-benzopyran-b-1l)-3- (KU MA-14-(M-benzyloxycarbonyl)amino-I "benzopyran-b -yl|-5-fluoro-M2-|3-0M- fluoro-M2-I3-(M- methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine and RA/C 1095 (5095 content of methylamino)carbonylmethyleneoxyphenium|- | water) suspended in MEOH and hydrogenated in a Parr apparatus for 14 hours (22 7C, so 2,4-pyrimidinlismine (K950421) pressure 2.7 atm). The suspension is filtered through celite and washed with MeOH.

The combined filtrates are concentrated under reduced pressure to obtain (К)-М44(4-

KkZz amino-1-benzopyran-b-yl)-5-fluoro-152-/3-(M-methylamino)carbonylethyleneoxyphenyl|-2,4- -y 7 42) ko 60 b5 pyrimidinediamine in the form of a white solid. IN NMR (0M50-46): 5 9.60 (5, 1H), 9.46 (5, 1H)), 8.73 (b5, ZN), 8.00-8.10 (ti, ZN), 7.47 (5, 1H), 7.42 (t, 1H), 7.29 (4, 1H, 457.2

Gi), 71 01.22 7.2 Hz), 6.824, 1H, 17.0 Sk), 6.46 st, IN), 4.23-4.46 (t, ZN), 4.31 (5,

ZNU, 2.63 (y, ZN, 7- 4.6 Hz), 2.09-2.29 (tyu, 2NU; LC/MS: purity: 98.60; MO (m/z): 437.20 (M 7.4198 Со) ma-|4-(M-tert» Equimolar mixture of (5) M4-14-(M-tert-butoxycarbonyl)amino-1-benzopyran-b-butoxycarbonyl)amino» I«benzopyran-b- yl|-2-chloro-5-fluoro-4-pyrimidinamine and b-amine sindazole in MEOH are mixed in yl|-5-fluoro-M2-(indazol-b-yl)-2,4- hermetically closed tube for 24 hours at 100 "С. As a result of aqueous treatment of pyrimidinediamine SK950422) a brown solid is obtained, which is purified by the method of column chromatography on silica gel with the formation of (4) M4-14-(M-tert-butoxycarbonyl)amino-I-benzopyran-6-yl| -5-fluoro-Mm2-(indazole-b-1l)-2,4-pyrimidinediamine in the form of a binary solid. LC/MS: purity: 92.790; MS (m/z): 490.23 (M). 7.4. 199 (Ce) ma4-(4-amino-1-benzopyran-b-yl-5- (U) ma-(4(M-tert-butoxycarbonyl)amino-1-benzopyran-b-1l|-5-fluoro- M2-(indazol-b-yl)-2,4-fluoro-M2-(indazol-b-yl)-2,4-pyrimidinediamine is suspended in dichloromethane and treated with trifluoroacetic acid pyrimidinediamine (К950423) The mixture is stirred for 30 minutes at 22 "С and concentrated to dryness under reduced pressure. The residue is neutralized with sodium bicarbonate and crystallized from

MeOH-water to give (1) M4-(4-amino-1-benzopyran-b-yl)-5-fluoro-M2-(indazol-b-yl)-2,4-pyrimidinylamine as a white solid. LC/MS: purity: 89.095; MS (m/z): 390.21 (M). 7.4.200 (C Ma-(4-amino-1-benzopyran-b-yl)-M2»- Mixture of equimolar amount (is) M4-I(4-(M-tert-butoxycarbonyl)amino-I-benzopyran-6 - 3,5-dichloro-4-methoxyphenyl)-z-fluoro-2,4- | 11|-2-chloro-5-fluoro-4-pyrimidinamine and 3,5-dichloro-4-methoxyaniline hydrochloride in MEON 19 lyrimidinediamine (2950424) are stirred in a hermetically closed tube for 24 hours at 1009 C. As a result of further treatment, a brown solid is obtained, which is purified by column chromatography on silica gel to give (7) Ma-(4-amino-1-benzopyran-b-yl) )-M2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine in the form of a white solid, and!

LMR (0M5O-46): 5 9.42 (5, 1NI), 9.33 (5, 1H), 8.08 (y, 1H, 3: 2.4 Hz), 7.76 (5, 28) . , 3.72 (5, ZN), 1.85-2.18 (t, 2H); LC/MS: purity: 97.39; MS (m/z); 448.12 (M. 74201 СО ma-(4-(Metret- Mixtures of equimolar amounts (5) M4-14-(M-tert-butoxycarbonyl)amino- I-benzopyran-b- butoxycarbonyl)amino- 1 "benzopyran-b - 1.2-chloro-5-fluoro-4-pyrimidinamine and 3.2-dimethoxyaniline in MEOH are mixed in 1.1-M2-(3,5-dimethoxyphenite)-5-fluoro-7,4- | 24 hours at 100 C. As a result of wave treatment of pyrimidinediamine (2950425) a brown solid is obtained, which is purified by column chromatography on silica gel to form (5) M4-14-(M-tert-butoxycarbonyl)amino-|-benzopyran-b- yl)-142-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine in the form of a white solid substance, which "NMR (0M50-46): 5 9.24 (5, 15), 8 ... (4, IN, 2 8.7 Gy), 6.03 (t, 10), 4.68 (t, 1H, 4.17 (t, 29), 1.80-2.05 (t, 2H)), 1.41 (5, 9H); LC/MS: purity: 93.990; MS (m/z): 510.24 (MU). Ge) 7.4.202 (2) ma-(4-amino-I-benzopyran- b-yl)-M2- (o Mm4-144(M-tert-butoxycarb onyl)amino-1-benzopyran-b-yl)-Mm2-(3,5-dimethoxyphenyl)-5-(3,5-dimethoxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine is suspended in dichloromethane and treated with trifluoroacetic pyrimidinediamine (K950426) acid. The mixture was stirred for 30 minutes at 22 "C and concentrated to dryness under reduced pressure. The residue is neutralized with sodium bicarbonate and crystallized from MeOH-water to form M4-(4-amino-1-benzopyran-b-yl)-M2-3,5-se dimethoxyphenium)-5-fluoro-2,4-pyrimidinediamine in the form of a white solid matter. LC/MS: purity: 93.15; MS (m/z): 210.23 (M). b 7.4.203 (Ce) Ma-I4-(M-tert- i Mixture of equimolar amount of (C) M4-(44"M-tert-butoxycarbonyl)amino-I"-benzopyran-b"butoxycarbonyl)amino-1-benzopyran -b- yl|-2-chloro-5-fluoro-4-pyrimidinamine and 3-chloro-4-methoxyaniline in MEON are mixed in il|-M2-43-chloro-4-methoxyphenyl)-5-fluoro- | in a hermetically closed tube for 24 hours at 100 "C. As a result of aqueous treatment, 2,A-pyrimidinediamine (950427) is obtained as a brown solid, which is purified by column chromatography on silica gel to form (4) M4-14-(M-tert -butoxycarbonyl)amino-1-benzopyran-b-yl|- sem 2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,2-pyrimidinediamine as a white solid. LC/MS: purity: 93, 70; MS (m/z): 514.21 (M. c 74204 (a Ma-(4-amino-1-benzopyran-beyl)-M2- (t) Ma4144(M-tert-butoxycarbonyl)amino-1-benzopyran- 6-yl)-M2-(3-chloro-4-methoxyphenyl)-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-5-fluoro-2,4-pyrimidinediamine is suspended in dichloromethane and treated with trifluoroacetic pyrimidinediamine (KO50428) with acid. The mixture is stirred for 30 minutes at 22 "C and concentrated to dryness under reduced pressure. The residue is neutralized with sodium bicarbonate and crystallized from MeOH-water to form (4) M4-(4-amino-1-benzothirane) -b-ip)-M2-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LC/MS: purity: 91.490; MS (m/z): « 414.13 (MU. 50 7.4.205 Co ma-I44 (M.tert- Mixture of equimolar amount of (3) M4-(4-(M-tert-butoxycarbonyl)amino-|-benzopyran -b- - c butoxycarbonyl)amino-1-benzopyran-b-|il)-2-chloro-5-fluoro-4-pyrimidinamine and 3,4-dichloroaniline in MEOH are mixed in il|nch2443,4-dichlorophenyl)-5 -fluorine 2,4- in a hermetically sealed tube for 24 hours at 1007. As a result of water treatment. n » pyrimidinediamine (К950429) a brown solid is obtained, which is purified by the method of column chromatography on silica gel to form (4) 44-(4-(M-tertbutoxycarbonyl)amino-1-benzopyran-b-yl|-

M2-(3,4-dichlorophenyl)-5-fluoro 2,4-pyrimidinediamine as a white solid.

RHLMS: purity: 86.795; MS (m/zu: 518.17 (M). 7.4.206 (y) ma4(4-amino-1-benzopyran-b-yl)-M2-Ce) ma-(4-(«M-tert-butoxycarbonyl )amino-1-benzopyran-b-11)-M2-(3,4-dichlorophenyl)-5-fluoro-

Go! (3,4-Lichlorophenia)-5-fluoro-2,4-2,4-pyrimidinediamine is suspended in dichloromethane and treated with trifluoroacetic acid. pyrimidinediamine (K950430) The mixture is stirred for 30 minutes at 22 "C and concentrated to dryness under reduced pressure. The residue is neutralized with sodium bicarbonate and crystallized from a drop of MeOH.water to form (5) M4-(4-amino-1-benzopyran) -b-yl)-M2-(3,4-dichlorophenyl)-5- -y 7 42) ko 60 b5 fluoro-2,4-pyrimidinedismine in the form of a white solid, LC/MS: purity: 88.30; MS

And PV EE

7.4.207 (x) M2-14-(M-tert-butoxycarbonylamino- | Sum of equimolar amount of 2-chloro-M4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidinamine 1-benzopyran-b-ylMa4- (3,5- and St) b-amino-4-(M-tert-butoxycarbonyl)amino-1-benzopyran in MEOH is mixed in dimethoxyphenyl)-5-fluoro-2,4- in a sealed tube for 24 hours at 100 S. As a result of aqueous treatment of pyrimidinediamine (K950437) a brown solid is obtained, which is purified by column chromatography on silica gel to form (xx) M2-(4-(M-tert-butoxycarbonyl)amino-I-benzopyran-b-yl|-

M443,5-limethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine in the form of a white solid.

LC/MS: purity: 97.295; MS (m/z): 510.3 (M). 7.4.208 (5) M2-14-(M-tert- Mixture of equimolar amounts of 2-chloro-M4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimilinamine and butoxycarbonyl)amino-1-benzopyran-b- (In b-amino-4-(M-tert-butoxycarbonyl)amino-1-benzopyran in MEOH is stirred in ily-Ma-(3,4-dichlorophenyl)-5-fluoro-2,4- hermetically sealed tube for 24 hours at 100 C. As a result of aqueous treatment of pyrimidinediamine (K950433), a brown solid is obtained, which is purified by column chromatography on silica gel to form (5) M2-(4-(0M-teri-butoxycarbonyl)amino- | -benzopyran-b -il|-

M4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine in the form of a white solid. /N

NMR (0M5O-46): 5 9.51 (in, 1H), 9.12 (5.1H), 8.12 (4, IN, 7- 2.4 Hz), 8.06 (9, IN, 75 3 ,6 Hz), 7.82 (t, IN), 7.49 (4, 1H, 7-8.7 Gy), 7.43 (t, 18), 7.32 (, IN, 159.0 Hz), 7.25 (t, 1H), 6.67 (0.1, P- 8.7 Gy), 4.12-4.65 (t, ZNU, 1.84-1.99 (n, 78), 1.40 (5.9H)U; LC/MS: purity: 91.25; MS (m/z): 518.3 (MU. 7.4.299 M2-(4(B,5)-0M-tert- A mixture of an equimolar amount of (5)-2-chloro-5-fluoro-M4-(2-methyl-3-oxo-4H-butoxycarbonyl)amino-I-benzopyran-b-benz|1,4 |oxazin-b-yl) -4-pyrimidinamine and (Sk) b-amino-44(M-tert-butoxycarbonyl)amino-yl|i-5-fluoro-M4-(245)-methyl-3-oxo-4H-1-benzopyran in MEON are mixed in a hermetically sealed tube for 24 hours, benz1,oxazin-6b-yl-2,4- at 100 2C. As a result of aqueous treatment, a brown solid is obtained, which pyrimidinediamine (K950434) is purified by column chromatography on silica gel to form M2-(14 -(8,5)-(M-tert-butoxycarbonyl)amino-1"benzopyran-b-yl|-5-fluoro-Ma4-124(5)-methyl-3-oxo-4H-benzi1,Zoxazin-b- il|-2,4-pyrimidinediamine in v the appearance of a white solid. LC/MS: purity: 89.395; MS (m/z): 537.42 (MN). 7.4.210 (5) M2-(4-amino-1-benzolyran-b-yl|-M4- | (53 M2-14-(M-tert-butoxycarbonylamino-1-benzoviran-6-1l)|-M4- (3,5-dimethoxyphenyl)-5-(3,5-dimethoxyphenyl)-5-fluoro-2,4-fluoro-2,4-pyrimidinediamine is suspended in dichloromethane and my pyrimidinediamine (K950436) is treated with trifluoroacetic acid. 30 minutes at 22 "C and concentrated to dryness under reduced pressure. The residue is neutralized with sodium bicarbonate and crystallized from MEeOH-water to form (Ce) M2-(4-amino-1-benzopyran-6-yl)- M4-(3 . -beylMa" | (9) M2-(4-(M-tert-butoxycarbonyl)amino-1-benzopyran-6-yl|D-M4-(3.4-lichlorophenyl)- 5-fluoro- and svt TE (3 ,4-Lichlorfenip)-5-fluoro 2,4-2,4-pyrimidinediamine is suspended in dichloromethane and treated with trifluoroacetic (o)pyrimidinediamine (K950437) acid. The mixture is stirred for 30 minutes at 22 "C and concentrated to dryness under reduced temperature claim The residue is neutralized with sodium bicarbonate and crystallized from MEOH-water to form (1) 142-(4-amino-i-benzopyran-b-yl)-M4-(3,4-dichlorophenyl)-5-fluoro 2,4-pyrimidinediamine. BY ME? (YUM5O-46): 5 9.51 (5, 1H), 8.99 (5, 18), 8.09 (a, TN, 7: 2.4 Hz), 8.07 (0, EN, 3 - 3.6 Gy), 7.45-7.81 (t, 2H), 7.30 (da, 1H, 3-24, "se 9.0 Hz), 6.62 (y, IN, 1 - 8.7 Gy), 3.78-4.20 (t, ZNU, 1.73-2.05 (t, 2H); LC/MS: purity: 10095; MS (m/z): 420.29 (M, 100). 7.4.213 M2-IK(B,5)-amino-1-benzopyran-6-yl)-5- 142-(4 (B,5)-(M-tert-butoxycarbonyl)amino- 1-benzopyran-5-yl|5-fluoro-M4-(2 (5)-methyl-3- (22 fluoro-m4-(2(5)-methyl-3-oxo-4H- oxogaNevenzi 1,4oxazine-b -yl)-2,4-pyrimidinediamine is suspended in dichloromethane and 1,oxazin-b-yl|-2,4- benzene is treated with trifluoroacetic acid. The mixture is stirred for 30 minutes at 22 or pyrimidinediamine (2950438) C and concentrated to dryness under reduced pressure. The residue is neutralized with sodium bicarbonate and crystallized from MeOH-water to form M2-H(K.5)-amino-1-sibenzopyran-b-1l)-5-fluoro-im4-(2(5)-methyl -Z-oxo-4 ben|i Yaoxazin-b-yl|-2,4- pyrcmidindiamine. LC/MS: purity: 97.999; MS (m/z); 435.37 (M). 7.4.214 M2-C18 ,28)-2-Aminocyclohex-1-yl)- Mixture 2- chloro-M4-3,5-dimethoxyphenyl)-5-fluoro-1-pyrimidinamine and 3 equivalents (KK). co

M443,5-dimethoxypheni)-5-fluoro-2,4-1,2-diaminocyclohexane in MEOH is stirred in a hermetically closed tube for 3 pyrimidinedimine (5950439) days at 100 C. As a result of aqueous treatment, a brown solid is obtained, which purified by methanol column chromatography on silica gel with the formation of M2-(C18.28)-2-aminocyclohex-1-yl)-M4-(3,5-dimethoxyphenyl)-5-fluoro-2-4-pyrimidinediamine. LC/MS: purity: 94.695; MS (m/z): 360.20 (M). « 7.4.215 M2-(I8,2K)-2-aminocyclohex-1-yl)-M4- | A mixture of M4-4(3,4-dichlorophenyl)-2-chloro-5-fluoro-4-pyrimidznamine and 5 equivalents of (KK)-12-(3,5-lichlorophenyl)-3-fluoro-2,4- of diaminocyclohexane in MEOH is stirred in a hermetically closed tube for three days at 100 °C. As a result of aqueous treatment, a brown solid is obtained, which is purified by column chromatography on silica gel to form M2-(I K2K)-2- aminocyclohex-1-yl)-M4-(3,5-vichlorophenyl)-5-fluoro-2,4-pyrimidinediamine. /"H NMR h - (0M5O-46): 5 9.49 (5, 1H)), 9, 26 (5, 1H), 8.02, 7.44-7.54 (t, ЗН), 6.81 (4, 1H, 1: 9.9 Hz), 3.31 " (t, TNU, 2 .78 (t, 1), 1.15-1.98 (t, 88); LC/MS: purity: 98.395; MS (m/z): 368.07 (M, 109). 7.4.216 142- (18,2K)-2-aminocyclohex" 1-17)-5- Mixture (5)-2-chloro-5-fluoro-M4-(2-methyl-3-oxo-2H-benz 1,4)oxazine- b-yl)-4-pyrimidinamine fugor-ma-1(25)-2-methyl-3-oxo-4H- and 5 equivalents of (K,K)-1,2-diaminocyclohexane in MeOH are mixed in hermetically sealed (ee) benz (1,4|oxazin-b-yl)-2,4- in a closed tube for 3 days at 100 "С . As a result of aqueous treatment, pyrimidinediamine (5950441) is obtained as a brown solid, which is purified by column chromatography on silica gel to form M2-(18,28)-2-aminocyclohex-1-1l)-5-fluoro-M4-1(25)- 2-methyl-3-oxo-4H-co benz|1,41oxazin-b-yl)-2,4-pyrimidinediamine. LC/MS: purity: 9.800; MSsim/3y 385.15. ShSHZ' -y 7 42) ko 60 b5 nysh 65 7.4.217 (8B.8)-M4-(4,4-dimethyl-1,3-dioxo- Mixture MA-(4,4-dimethyl-1,3- dioxo-2H,4H-isoquinolin-7-yl)-2-chloro-5-fluoro-4- .K)-1,2-diaminocyclohexane in MeOH is stirred in aminocyclohexane-1-yl)-2,4- hermetically closed tube for 3 days at 100 "C. As a result of aqueous treatment of pyrimidinediamine (KU50442) a brown solid is obtained, which purified by column chromatography on silica gel to form (KK)-M4-(4,4-dimethyl-1,3-diaxo-2H.4H-isoquinolin-7-yl)-5-fluoro-M2-(2-aminocyclohexane-1 -yl)-2,4-pyrimidinediamine, RHLMS: purity: 92195; MS "(m/zu 411.14 (M). 74218 M24(1K,28)-2-aminocyclohex-1-yl)-5- Suminyl CE)-2-chloro-MA-12-(2-hydroxy)ethyl-3-oxo-4H-benzi 1,4 |oxazin-b-yl|-4-fluoro-Ma-(2K,5)-2- (2-hydroxy)ethyl-3-pyrimidinamine and 5 equivalents of (K,K)-1,2-disaminocyclohexane in MEeOH oxo-4H-bene 1 4|oxazin-b-yl-2,4- are mixed in a hermetically closed tube on Ave loads From days at 100 "C. As a result of pyrimidinediamine (5950443) aqueous treatment, a brown solid is obtained, which is purified by column chromatography on silica gel to obtain M2-(18.2К)-2-aminocyclohex-1-1l)-5-fluoro-4-85) 2- (2-Tihydroxy)ethyl-3-oxo-4H-benzyl-1-Coxazin-b-yl)-2,4-pyrimidinediamine.

RF/MS: purity; 86.15; MS (m/z): 415.17 (M). 74219 Ma-(3,5-dimethoxyphenyl)-12-I4-(2-M,M- Mixture of equimolar amount of 2-chloro-M4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidinamine diethylaminoethyleneamino)carbonylphenyl | and 4-((2-M,M-diethylaminoacetylenamino)carbonylaniline in MEeOH are mixed in -5-fluoro-2,4-pyrimidinediamine (VK950444) | in a hermetically closed tube for 3 days at 100 "C. As a result of aqueous treatment, a brown solid substance, which is purified by column chromatography on silica gel to form М4А-(3,5-dimethoxyphenyl)-М2-14-(2-М,М-distillaminoethyleneamino)carbonylphenyl)-5-fluoro-2,4-pyrimidinediamine. РХ/ MS: purity: 89.15, MS (m/z), 481.19 (M). (3,4-dichlorophenyl)-5-fluoro-4-pyrimidinamine and 4-diethylaminostildenamino)carbonylphenyl! | ((2-M,M-distillaminostylenamino)carbonyl|aniline in MEON is mixed in hermetically -5-fluoro 2,4-pyrimidinediamine (K950445) | in a closed tube for 3 days at 100 C. As a result of wave treatment, a brown solid is obtained, which is purified by column chromatography on silica gel to form M4-4(3,4-dichlorophenyl)-M2-1442-MM-diethylaminoethyleneamino )carbonylphe nil|-3-fluoro-2,4-pyrimidinediamine. LC/MS: purity: 93.25; MS (m/z): 489.12(M). 7.4.221 (5)4m2-(1442-M,M- Suming equimolar amount of (5)-2-chloro-5-fluoro-M44(2-methyl-3-oxo-4H- diethylaminoacetylenamino)carbonylphenyl| | benzene 1.5 )oxazine-6-1l)-4-pyrimidinamine and 4-((2-M.M- -5-fluoro-M4-(2-methyl-3-oxo-4H- diethylaminoacetylenamino)carbonyl|aniline in MEOH are mixed in a sealed closed benz 1,4 |oxazineb-yl)-2,4 tube for 3 days at 109 C. As a result of aqueous treatment, a brown pyrimidinediamine (K950446) solid substance is obtained, which is purified by column chromatography on silica gel for

M formation of (5)-M2-(4-(2-M M-diethylaminoethyleneamino)carbonylphenyl)-5-fluoro-Ma-(2-methyl- se

SHY Zgokso-AN-benz| and Poxazne-6-1α)-2,4-pyrimidinediamine. RHLME: purity: 93.99: MS o (m/z): 506.15 (M). 7.4.222 MA-(4,4-dimethyl-1,3-dioxo-2H.4H- Mixture of an equimolar amount of M4-(4,4-dimethyl-1,3-dioxo-?2H.4H.isoquinolin-7-yl) )-2-chloro-isoquinoline 7-1l)-5-fluoro-m2-(4-(M,M-5-fluoro-4-pyrimidinamine) and 1-amino-4-(MM-distillaminoacetyleneaminocarbonyl)benzene to diethylaminoethyleneaminocarbonyl )phenyl| | MeOH is stirred in a hermetically closed tube for 3 days at 100 C. In -2,4-pyrimidinediamine (2950447) as a result of aqueous treatment, a brown solid is obtained, which is purified by column chromatography on silica gel to form M4-(4, 4-Dimethyl-|,3-dioxo"(Ce)2NAH-isoquinolin-7-yl)-5-fluoro-M2-14-4M,M-diethylaminoethyleneaminocarbonyl)phenyl|-2,4- pyrcmidindiamine. YIN YAM? (0РМ5О-46):6 11.32 (5, 1Н), 9.96 (5, IN), 9.70 (в, 1Н), 9.55 (5, (е») 1Н), 8.66 (t, 1), 7.67-8.24 (t, 7), 3.59 (t, 2H), 3.17 (tt, 6H), 1.53 (v, 6, 1.22 (6 5Н, 2- 7.2 Gu РХ/MS: purity: 94.70; MO (m/z): 532.21 (MU. "-- 7.4.223 Со" M2-44402-М,М- A mixture of equimolar amounts . -M,M- c -5-fluoro-Ma-|(2-hydroxystyl)-3-oxo-4H- |diethylaminostylenamino)carbonyl|aniline in MEON is stirred in a hermetically sealed benz1,4oxazine-b-yl-2,4- tube for 3 days at 190 "C. As a result of water treatment, a brown color is obtained

C5 pyrimidinediamine (KU50448) solid substance, which is purified by the method of column chromatography on silica gel for the formation of (t)-M2-14-(2-M,M-diethylaminoacetylenamino)carbonylphenyl |- 5 fluoro-4-(2- hydroxyethyl )-3-oxo-4H-benzi 1,4 oxazine-6-1l)-2,4-pyrimidinediamine. RQZ/MS: purity: 93.792; MS (m/z): 536.17 (M). 7.4.224 M2-(4-(2-M,M- Mixture of an equimolar amount of 2-chloro-M4-(2,2-difluoro-3-oxo-4H-benz| I,oxazin-b-iya)-5- distylaminoacetylenamino)carbonylphenyls | fluoro-2,4-pyrimidinamine and 4-1(2-M,M-diethylaminoethyleneamino)carbonylaniline in MEON "-M44(2,2-difluoro-3-oxo-4H-) are mixed in a hermetically sealed tube under a draft From days at 100 C. As a result of aqueous treatment of benzol 1,NDoxazin-b-yl)-5-fluoro-2,4-, a brown solid is obtained, which is purified by the method of column - pyrimidinediamine (KU50449) chromatography on silica gel to form M2- (4-(2-М,М-с diethylaminoethyleneamino)carbonylphenyl-М4-(2,2-difluoro-3-oxo-41-benz 1,oxazineb-yl)-5-fluoro-2,4-pyrimidinediamine. РХ/ MS: purity: 86.805; MS (m/3): 528.18 (M). ; - 7.A.225 1M2-(4-aminocarbonylphenyl)-M4-(3,5- Sum of equimolar amount of 2-chloro-M4 -(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidinamine dimethoxyphenyl)-5-fluoro-2,4- and 4-aminocarbonylaniline in MEOH are mixed in a hermetically sealed tube over pyrimidinediamine (K950450). From days at 100 C . As a result of wave treatment, a brown solid is obtained, which is purified by column chromatography on silica gel to form M2-(4-aminocarbonylphenyl)-M4-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. "H YAMI so (0М50-46); 5 10.34 (5, 1), 10.14 (5, 1), 8.30 (8, 1Н, 3-24 Hz), 7.75 (4, 2Н , 1: 9.0 Gy), 7.624, 2H, 3- 8.7 Gy), 7.25-7.35 (t, 2), 6.90 (t, 2H)), 6.35 (t, 1) .

7.4.226 M2-(4-aminocarbonylphenyl)-M4-(3,4- A mixture of equimolar amounts of 2-chloro-M4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidinamine and 4-dichlorophenyl)-5- fluoro-2,4-aminocarbonylaniline in MEOH is stirred in a hermetically sealed tube for 3 pyrimidinediamine (59502451) days at 100 "C. As a result of aqueous treatment, a brown solid is obtained, which is purified by column chromatography on silica gel to form M2-(4- aminocarbonylphenyl)-Ma4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine. LC/MS: purity: 93.992; MS (m/z): 399.09 (M). 7.A4.227 (5)-M2-(4-aminocarbonylphenyl)-5-fluoro- | A mixture of an equimolar amount of (5)-2-chloro-5-fluoro-M44(2-methyl-3-oxo-4H-

M4-(2-methyl-3-oxo-4H-benz 1, Yaoxazin-b-yl)-4-pyrimidinamine and 4-aminocarbonylaniline in MEOH are mixed with benz| 1,4 oxazin-b-yl)-2,4- in a hermetically sealed tube room during the night at 100 C. As a result of aqueous treatment of pyrimidinediamine (950452) a brown solid is obtained, which is purified by column chromatography on silica gel to form (5 )-M2-(4-aminocarbonylphenyl)-5-fluoro-144-(2-methyl-3-oxo-4H-benz(1,4|)oxazin-b-yl)-2,4-pyrimidinediamine. LC/MS: purity: 92.39; MS (m/z): 70 407.18 (MU, 7.A228 Ma-(4,4-dimethyl-1,3-dioxo-2H.AN- A mixture of an equimolar amount of M4-(4,4-dimethyl-1, 3-dioxo-2H, 4H-isoquinoline-7-yl)-2-chloro-isoquinolin-7-yl)-5-fluoro-M2-(4-5-fluoro-4-pyrimidinamine and 1-amino-4- of aminocarbonylbenzene in MEOH is mixed in a hermetically closed tube of aminocarbonylphenyl)-2,4- for 3 days at 100 "C. As a result of aqueous treatment of pyrimidinediamine (KU50453) a brown solid is obtained, which is purified by column chromatography on silica gel to form M4-(4 ,4-dimethyl.1,3-dioxo-7H,4-isoquinoline7-yl)-5-fluoro-M2-(4-aminocarbonylphenyl)-2,4-pyrimidinediamine. LC/MS: purity: 92.290; MS (m/ z); 433.17 (M). 7.4.229 (5-M2-(4-aminocarbonylphenyl)-5-fluoro- | A mixture of an equimolar amount of ()-2-chloro-M4-|(2-hydroxyethylene)-3- oxo-4H-

MA (2-tihydroxyethylene)-3-oxo-4H-benz|1,4|oxazin-6-yl|-4-pyrimidinamine and 4-aminocarbonylaniline in MEON mix benz| 1,4 oxazine-b-1l)-2,4- in a hermetically sealed tube for 3 days at 100 C. As a result of aqueous treatment of pyrimidinediamine (KU50454), a brown solid is obtained, which is purified by column chromatography on silica gel to form (- -)-M2-(4-aminocarbonylphenyl)-5-fluoro-M4-((2-tihydroxyethylene)-3-oxo-4H-benzi I oxazine-6-1l1-2,4-pyrimidinediamine. LC/MS: purity: 90.49; MS (m/z): 437.14 (MU. 7.4.230 M2-4-aminocarboniaphenyl)-M4-(2,2- A mixture of an equimolar amount of 2-chloro-M4-(2,2-pifluoro- 3-oxo-4H-benz(1,4 z oxazine-6-11)-5-difluoro-3-oxo-4H-benz and Moxazin-b-fluoro-4-pyrimidinamine and 4-aminocarbonylaniline in MEOH are mixed in a hermetically sealed )-5-fluoro-2,4-pyrimidinediamine in a closed tube for 3 days at 100 "C. As a result of aqueous treatment, a brown solid (KO50455) is obtained, which is purified by column chromatography on silica gel to form M2-(4-aminocarbonylphenyl) -M4-4(2,2-difluoro-3-okoso-4H-benzi I 4 |oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine. LC/MS: purity : 90,896; MS (m/z): 429.14 (M). 7.4.231 Mm2-(144(M-tert- Mixture of equimolar amounts of 2-chloro-M443,5-dimethoxyphenyl)-5-fluoro-4-lyrimidineamine se butoxycarbonylamino)methylenephenyl|- and 4-(tert-butoxycarbonylaminomethylene)aniline in MeOH stir in hermetically and

M44(3,5-dimethoxyphenyl)-5-fluoro-2,4- in a closed tube for 3 days at 100 C. As a result of aqueous treatment, (o)pyrimidinediamine (5950456) is obtained as a brown solid, which is purified by column chromatography on silica gel for the formation of Ч2-(4-(P-tert-butoxycarbonylamino)methylenephenyl|-M4-(3,5-dimethoxyphenyl)-z"-fluoro-2,4-pyrimidinediamine. LC/MS: purity: 84.395; MS (m/ z): 468.26 (M. 74232 742-14-(M-tert- Mixture of equimolar amounts of 2-chloro-M4-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidinamine and 4-(Che)butoxycarbonylamino )methylenephenyl|- (tert-butoxycarbonylaminomethylene)aniline in MeOH is stirred in a hermetically closed

M4-(3,4-lichlorophenyl)-5-fluoro-2,4- tubes for 3 days at 100 C. As a result of aqueous treatment, a brown Teh! pyrimidinediamine (KU50458) solid, which is purified by column chromatography on silica gel to form M2-14-(M-tert-butoxycarbonylamino)methylenephenyl|. M4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine. LC/MS: purity: 91.39; MS (m/z): 476.13 (M), or 7.4.233 (5)A-M2-144(M-tert- A mixture of equimolar amounts of (5)-2-chloro-5-fluoro-M4-(2 -methyl-3-oxo-4H-benz I 4 oxazine-butoxycarbonylamino)methylenephenyl|-5- /| 6-yl)-4-pyrimidinamine and 4-(tert-butoxycarbonylaminomethylene)aniline in MEON sem fluoro-M4-(2- methyl-3-oxo-4H- is stirred in a hermetically closed tube for 3 days at 100 C. As a result of benzo(3,4-Euxazin-b-yl)-2,4- aqueous treatment, a brown solid is obtained, which is purified by column with pyrimidinediamine (KU50460) chromatography on silica gel for the formation of (5)-M2-14-(M-tert-butoxycarbonylamino)methylenephenyl-5-fluoro-M4-(2-methyl-3-oxo-4H-benzi and 4|oxazine- 6-yl)-2,4-pyrimidinediamine. LC/MS: purity: 93.596; MS (m/z): 493.22 (M). 7.4.234 M2-14-(M-tert- Sum of an equimolar amount of MA- (4,4-Dimethyl-1Z-lioxo-2H,4H-isoquinoline-7-1l)-2-chloro-butoxycarbonylamino)methylenephenyl|- 5-fluoro-4-pyrimidinamine and 4-amino-N-tert-butoxycarbonylbenzylamine in MEON

M4A4(4,A-dimethyl-|,3-dioxo-2H.YAN- is stirred in a hermetically sealed tube room for 3 days at 100 "C. As a result, "isoquinolin-7-yl)-5-fluoro-2,4- after aqueous treatment, a brown solid is obtained, which is purified by column 406 pyrimidinediamine (5950462) chromatography on silica gel to form M2-14-(M-tert-butoxycarbonylamino)methylenephenyl-Х4-(4,4-dimethyl-1,3-dioxo- 2H.4H-isoquinoline-7-1l)-c 5-fluoro-2,A-pyrimidinediamine. HPLC: purity: 92.29; MS (m/z): 519.21 (M", 100). p 7.4235 M2-144(M.tert- Mixture of equimolar amounts of 2-chloro-M4-(2,2-difluoro-3-oxo-4H-benz|1,4|oxazin-b-yl)-5- and 2-butoxycarbonylaminomethylene )phenyl|- fluoro-4-pyrimidinamine and 4-(tert-butoxycarbonylaminomethylene)gnilin in MEON

M4-(2,2-difluoro-3-oxo-4H-) is moved in a hermetically sealed tube for 3 days at 100 C. As a result, benzo(1,4-uxazin-.6-yl)-5-fluoro-2,4 - after aqueous treatment, a brown solid is obtained, which is purified by cholon pyrimidinediamine (4950464) chromatography on silica gel to form M2-(4-(M-tert-butoxycarbonyliminomethylene)phenyl|-ma-(2,2-difluoro-3-oxo-4H) -benzi I Poxazin-6-yl)-5-

Go! fluoro-2,4-pyrimidinediamine. LC/MS: purity: 89.29; MS (m/z); 515.18 (M). 7.4.236 М2-(4-aminomethylenephenyl)-м4-(3,5- 2-(4-(M-tert-buoxycarbonylamino)methylenephenyl)-М4-(3,5-dimethoxyphenyl)-5-fluoro-2,4 - ko dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine is suspended in dichloromethane and treated with trifluoroacetic acid. pyrimidinediamine (K950457) The mixture is stirred for 30 minutes at 22 "C and concentrated to dryness under -y 7 42) ko 60 b5 under reduced pressure. The residue is neutralized with sodium bicarbonate and crystallized from MEOH-water to form M2-(4-aminomethylenephenyl)-MA-(3,5-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LC/MS: purity: 92.29; MS (m/z): 368.20 (M. 7.4.237 M2-(4-aminomethylenephenyl)-Ma-(3,4- M2-14-4(M-tert-butoxycarbonylamino)methylenephenia |- 4-(3,4-dichlorophenyl)-5-fluoro-2,4-dichlorophenyl)y-5-fluoro-2,4-pyrimylindigmine is suspended in dichloromethane and treated with trifluoroacetic acid. 2 pyrimidinediimine (K950459) The mixture is stirred for 30 minutes at 22 C and concentrated to dryness under reduced pressure. The residue is neutralized with sodium bicarbonate riyu and crystallize from

MmeOH-water for the formation of M2-(4-aminomethylenephenyl)-M4-(3,4-dichlorophenyl)-5-fluoro-2,4-pyrimidinediamine. LC/MS: purity: 94.095; MS (m/z): 376.06 (M). 7.4.238 (5)-M2-(4-aminomethylenephenyl)-5-fluoro" (8)AM2-(4-(M-tert-butoxycarbonylamino)methylenephenyl)-5-fluoro-M44(2-methyl-3-oxo -4H-m4-(2-methyl-3-oxo-4H-benzyl(1,4|oxazin-b-yl)-2,4-pyrimidinediamine is suspended in dichloromethane and treated with benzyl 1,4 |oxazin-6-yl) -2,4- trifluoroacetic acid. The mixture is stirred for 30 minutes at 22 C and pyrimidinediamine (K9504611) is concentrated to dryness under reduced pressure. The residue is neutralized with sodium bicarbonate and crystallized from 3 MeO-water to form (5)-М24(4- aminomethylenephenyl)-5-fluoro-M442-methyl-3-oxo-4Nebenzi I,4|oxazin-b-yl)-2,4-pyrimidinediamine. LC/MS: purity: 94.76; MS (m/z): 393.15 (MI). 7.4.239 M2-(4-aminomethylenephenyl)-3х4-(4,4-a-4(4,4-methyl-1,3-dioxo-2H,4H-isoquinolin-7-yl)-5-fluoro- M2-14-(M-tert-dimethyl-1,3-dioxo-2H,4H-isoquinoline-7-butoxycarboylaminomethylene)phenyl)-2,4-pyrimidinediamine is suspended in dichloromethane and 5-fluoro-2,4-pyrimidinediamine is treated trifluoroacetic acid. The mixtures are stirred for 30 minutes at (K950463) 22 7C and concentrated to dryness under reduced pressure. The residue is neutralized with sodium bicarbonate and crystallized from MeOH-water to form M2-(4-aminomethylenephenyl)-M4-(4,4-dimethyl-1,3-dioxo-2H,4H-isoquinoline7-yl)-5-fluoro-2, 4- pyrimidinediamine. LC/MS: purity: 92.396; MS (m/z): 41949 (MO). 74240 M2-(4-aminomethylenephenyl)-ma42,2-142-I4-4(M-tert-butoxycarbonylaminomethylene)phenyl-M4-(2,2-difluoro-3-oxo-4H-difluoro-3-oxo-4H- benzyl 1,4-oxazin-6-benzyl 4-oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine is suspended in dichloromethane and yl)-5-fluoro-2,4-pyrimidinediamine is treated with trifluoroacetic acid. The mixture is stirred for 30 minutes at (8950465) 29 "C and concentrated to dryness under reduced pressure. The residue is neutralized with sodium bicarbonate and crystallized from MeOH-water to form M2-(4-aminomethylenephenyl)-Ma-(2,2-difluoro -3-oxo-4H-benzyl 1,4-oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine. LC/MS; purity: 93.96; MS (m/z); 415.3 ( M). 17.4.241 M44(3,5-limethoxyphenyl)- M2-(3-MM- A mixture of an equimolar amount of 2-chloro-M4-(3,5-dimethoxyphenyl)-5-fluoro-4-virimidinamine diethylaminopropyl)- 5-fluoro-2,4- and 3-M,.M-diethylaminopropylamine in MEON is stirred in a hermetically closed tube on pyrimidinediamine (KU50469) for 3 days at 100 C. As a result of aqueous treatment, a brown solid is retained, which is purified by column chromatography on silica gel for the formation of ss Ma-(3,5-dimethoxyphenyl)-M2-(3-M-diethylaminopropyl)-5-fluoro-2,4-pyrimidinediamine. with higher LC/MS: purity: 94.392; MS (m /z): 378.33 (MH). Ho) 7.A.242 M4-(3,4-lichlorophenyl)-M2-(3-M,M- Mixture of an equimolar amount of 2-chloro p-M443,4-dichlorophenyl)-5-fluoro-4-pyrimylamine and 3-diethylaminopropyl)-2-fluoro-2,4-MM-diethylaminopropylamine in MeOH are stirred in a hermetically sealed tube on pyrimidinediamine (K950470) for 3 days at 100 C. As a result of the wave treatment, a brown solid is obtained, which is purified by column chromatography on silica gel to form ma-(3,4-dichlorophenia)-M2-(3-M,M.distillaminopropyl)-3-fluoro-2, 4-pyrimidinediamine. (Che) from RH/MS: purity: 10095; MS (m/z: 386.18 (MH). 7.2.243 (5)-M2-(3-M,M-distillaminopropyl)-5- A mixture of an equimolar amount of (5)-2-chloro-5-fluoro-M4 -(2-methyl-3-oxo-4H-(o)fluoro-M4-(2-methyl-3-oxo-4H-benzyl, oxazine-6-11)-2,4-pyrimidinamine and 3-M, M-diethylaminopropylamine in MEOH benz/1,oxazin-6-yl)-2,4- is stirred in a hermetically sealed tube for 3 days at 100 "C. As a result of "-- pyrimidinediamine (950473) aqueous treatment, a brown solid is obtained, which purified by column chromatography on silica gel to form (5)-M2-(3-M,M-diethylaminopropyl)-5-fluoro-MA.(2-methanal-3-oxo-4H-benz|1,4oxazine-b-1l )-2,4-pyrimidinediamine. LC/MS: purity: 85.3; se

MS (m/zu; 403.34 (MN).

Zo 74244 MA-4,4-dimethyl-1,3-dioxo-2H,AN- A mixture of an equimolar amount of M444,4-dimethyl-1,3-dioxo-2H,4H-isoquinoline7-zl)-2-chloro" (he ) isoquinolin-7-yl)-M2-(3-MM. 5-fluoro-4-pyrimidinamine and 3-M,M-diethylaminopropylamine in MEOH are mixed in diethylaminopropyl)-5-fluoro-2,4- hermetically closed tube in a draft From days at 100 C. As a result of wave treatment of pyrimidinediamine (K950472) a brown solid is obtained, which is purified by column chromatography on silica gel to form M4-(4,4-dimethyl"1,3-dioxo-2H.4H-isoquinoline" 7 -17). M2-(3-MM-diethylaminopropyl)-5-fluoro-2,4-pyrimidinediamine. LC/MS: purity: 95.95; MS (m/z) in: « 429.51 (ME). 7.a4.245 (1)-5-fluoro-M2-Y3-(M- Solution (x)-M4-44-amino-I-benzopyran-6b«1l1)»5-fluoro-M2»(3-0M » -o methylamino)carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine in THF:DMF is treated with Na-M-(M-p-toluenesulfonyl)amino-1-toluenesulfochloride and triethylamine. The mixture is stirred for 1 hour at benzopyran-b-yl)-2,4-pyrimidinediamine OS and diluted with hexadec. The reaction mixture is filtered, and the solid residues are dried " » (8950493) and subjected to column chromatography to form ()-5-fluoro-M2-|3-(M-p methylamino)carbonylmethyleneoxyphenyl|- M4-(440h-p-toluenesulfonyl)amino - 1-benzopyran-b-yn)-2,4-pyrimidinlyemiva in the form of a white solid substance. "H YAM? (0М50-46): 6 9.24 (5, IN), 9.00 (5, IN), 8.01 (4, 18, 722.4 Go), 8.16 ska, IN, 15 7.8 Hz), 7.63-8.05 (t, 4H), 7.21-7.37 (t, ZNO), 7.08 (i, 1H, 1- 7.8 Hz), 6.694, 1H, 15 8.4 Ha), 6.46 (0, 1H, 7: 6.9 Hz), 4.40 (t, 1H0O, 4.29 (5, IN), 4.10 (t, 2H)), 3 .33 (5, ZNI), 2.64 (5, ZNU, 1.88-2.08 (it, 2H); LC/MS: purity: 94055; MS (m/1): 591.16 (M ). 7.4.246 (y)-2-chloro-5-fluoro-Mma-(4-(M- A solution of (-)-4-amino-b-nitro-I-denzopyran in DMF is treated with triethylamine and

Kkz methanesulfonyl)amino-I-benzopyran-b-methanesulfochloride. The mixture is stirred for 30 minutes at 0 C and diluted with yl)-4-pyrimidinamine dichloromethane. As a result of aqueous treatment, the desired (2)-4-(0M4- -y 7 42) ko 60 b5 methanesulfonyl)amino-6-nitro-1-benzopyran is obtained in the form of a yellow solid. This solid and RY/C (1095) are suspended in MeOH and the resulting mixture is hydrogenated at 22 °C for 5 hours (2.7 atm pressure). The mixture is filtered and concentrated to dryness to give (1-)-4-( M-methanesulfonyl)amino-b-amino-1-benzopyran in the form of a brown oil, which is reacted with 2,4-cyclo-5-fluoropyrimidine in

MEeoN for 2 hours at 70 C. The mixture is diluted with water and the formed precipitate is filtered to form ()-2-chloro-5-fluoro-144-14-(M-moethanesulfonyl)amino-1-benzopyran-6-yl)-4 -pyrimidinamine in the form of a pale yellow solid. LC/MS: purity: 91.30; MS (m/z): 373.02 (MN). 7.4.247 (1)-5-fluoro M4-(44M- Solution of an equimolar amount of (-)-2-chloro-5-fluoro-M4-(4-(M-methanesulfonyl)amino-1-methanesulfonyl)amino- I1- benzopran-b-benzopyran-b-yl)-4-pyrimidinamine and 3-(M-methylamino)carbonylmethyleneoxyaniline yl)-m2-(34(M- is dissolved in MeOH and heated in a sealed tube at 110 C for 24 methylamino) carbonylmethyleneoxyphenyl|- | hours. As a result of aqueous treatment, ()-5-fluoro M4-14-(M- 70 2,4-pyrimidinediamine (950494) methanesulfonyl)amino- | -benzopyran-b-yl)-M2-13- (M-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine as a white solid. "H NMR (OM5O-46): δ 9.33 (5, 180), 8.91 (5, 1H), 8.03 (d, INN, 4: 2.4 Hz), 7.94 (t,

YIN 7.78 (t, IN), 7.66 (y, IN, 7: 8.4 Gy), 7.22-7.62 (t, ZN), 7.09 (5, 1H, 1- 8.1 Gy), 6.724, 1H,1- 8.7 Hz), 6.45 (18 each), 4.56 (t, 1H), 4.32 (5, 2H), 4.17 (t, 2), 3.29 (5, ZY), 2.65 (5,

ZNU, 1.75-2.16 (t, 2H); LC/MS: purity: 95.695; MS (m/z)y; 515.05 (M). 7.A.248 (-ма4-(А4-MA(М M. Solution ()-ма4-(4-amino-1-benzopyran-b-yl)-5-fluoro-М2-(3-(М- dimethylaminomethylenecarbonylamino -1- | methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine and M,M-diaminoglycine in benzopyran-b-yl-5-fluoro-M2-(3-(0Mch- DMF is treated with RuVgoR, and then with diisopropylethylamine. The mixture is stirred at methylamino )carbonylmethyleneoxyphenylI- | for 30 minutes at 22 "C and diluted with hexane. Sumin is filtered, and the volatile 2,4-pyrimidinediamine (К950416) residue is dried and subjected to column chromatography to form (5)-М4-14-М-(М,М .Dimethylaminomethylenecarbonyl)amino-I-benzopyran-6b-yl-5-fluoro-M2-(3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinedismine as a white solid. LC/MS: purity: 95.66; MS (m/zu: 522.26 (M). 7.424549 Su-ma-(A-M-(K M. Solution ()-M44(4-amino-1-benzopyran-6-1l)-5-fluoro- M2-13-(M-dimethylaminomethylenecarbonyl)-M-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine and M.M-divaminoglycine U methylamino-|-benzopyran-b-yl|-5-fluoro- D MF is treated with RuVgoR and then treated with isopropylethylamine. The mixture is stirred on

M2-I3-(M- for 30 minutes at 22 "С and diluted with hexane. The mixture is filtered, and the solid methylamino)carbonylmethyleneoxyphenyl- | residue is dried and subjected to column chromatography to give (4)-144-(4-М4(М,М - 2,A-pyrimidinediamine (К950419) dimethylaminomethylenecarbonyl)-M-methylamino-1-benzopyran-b-yl |-5-fluoro-M2-(3-(M-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine in the form of a white solid substances. H NMR (0M50-46, 2 rotamers): δ 9.28 (in, IN), 9.19 (8, 18), 9.03 (5, 18), 8.92. and5,

Y IN), 7.01-8.04 (14H), 6.74 (b, 2H, 19.0 Gy), 6.45 (t, 2H), 5.80 (t, IN), 5.51 (t , IN), 4.08- se 29 4.31 (t, 8H), 3.15-3.39 (t, 410), 3.32 (5, 61), 3.30 (5, ZY), 3.27 (t, 31), 2.645.6NH 90 Ge) 2.12 (t, 4H)U, LC/MS: purity: 94.395, MS (m/z): 536.30 (MG). 7.4.250 Ma-cyclopropyl-5-fluoro-M2-(4- Analogously to 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, morpholinophenyl)-2,4-pyrimidinediamine 2- chloro-M4-cyclopropyl-5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4- (K945356) dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) and cyclopropylamine (50 mg).

Similarly to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenip)-2,4-se pyrimidinediamine, M4-cyclopropyl-5-fluoro-M2-(4-morpholinophenyl)-2, 4-virimidinediamine is obtained as a result of the reaction of 4-morpholinoaniline (150 mg) and 2-chloro-M4-cyclopropyl-5-fluoro-4-pyrimidinamine (100 mg). YIN YAM? (SOSIZ): 5 0.63 (t, 7H), 0.88 (t, 2H), 2.82 (t, (22) 18), 3.10 (,1- 2.8 Gy, 45, 3 ... 55 (y, 1- 90 Hz, 2H), 7.74 (4, 1- 3.6 Go, IN); 19E NMR (282 MHz, SOS): 8 - y 169.88; LC/MS: retention time : 7.13 min.; purity: 91.6195; MS (m/z): 330.26 (MH). 7.4251 M2-cyclopropyl-5-fluoro-M4-(4- Analogous to the preparation of 2-chloro-M4-( 3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, morpholinophenyl)-2,4-pyrimidinediamine 2-chloro-5-fluoro-M4-(4-morpholinophenyl)-4-pyrimidinamine is obtained as a result of the reaction

Zo (8945357) at room temperature of 2,4-dichloro-5-fluoropyrimidine (300 me, 1.8 mmol) and 4-(he)morpholinoaniline (200 mg).

Similar to the preparation of MA-(3,4-ethylenedioxyphenial)-5-Fluoro-M2-(3-hydroxyphenyl)-2,4. pyrimidinediamine, M2-cyclopropyl-5-fluoro-M4-(4-morpholinophenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of cyclopropylamine (200 mg) and 2-chloro-5-fluoro-Ma-(4-morpholinophenyl)-4 -pyrimidinamine (100 mg). YIN YAM (SAUSAGE): 6 0.52 (t, 2), 0.77 (t, « 2), 2.69 (t, 180), 3.12 (6, 2- 4.8 Gu, 4H) , 3.85 (1, 15 4.8 Hz, AN), 5.16 (8, 1H), 6.66 (5, 1H), 6.89 (4.22 9.0 Hz, 2NI), 7 .60 (d, 7-9.0 Hz, 2H), 7.84 (, 7: 3.6 Gy, 1NU; I9E NMR (282 MHz, shsh

SOSI3U 8,170.72; RHLIS: retention time: 6.77 min.; purity: 88.8796; MS (m/z); s 330.22 (МН. h з» 7.4.252 M2-cyclobutyl-5-fluoro-M4-(4- Analogous to the preparation of IM4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)- 2,4-" morpholinophenyl)-2,4-pyrimylindiamine of pyrimylindiamine, M2-cyclobutyl-5-fluoro-Ma4-(4-morpholinophenyl)-2,4-pyrimidinediamine (K945358) is obtained as a result of the reaction of piclobutylamine (200 mg) and 2 -chloro-5-fluoro-M4-4-morpholinophenyl)-2-pyrimidinamine (100 mg). 1H NAM (SOS): 6 1.68-1.90 (t, 4H), 2.34- 2.53 ( t, 2H)), 3.14 (b, 34-4.8 Go, NU, 3.87 (i, 324.8 Hn, 4), 4.32 (t, 72 7.8 Hz, 1), 5.18 (5, (ee) IN), 6.61 (5, 19), 6.92 (8, 7-9.0 Hz, 2H), 7.53 (0.1- 9.0 Gy, 2H)), 7.78 (4, 7": 3.6 Gu, IN; I9E

YAM (282 MGy, SOSIZu: 6 "171.07; LC/MS: retention time: 8.05 min.; purity: z 79.6998; MS (m/z): 344.22 (MN). -y 42 ) 60 b5

7.4.253 m2-I3-(M-3-(Methoxycarbonylmethyleneoxy)nitrobenzene (2 g), cyclopropylamine (1 g) and triethylamine cyclopronylamino)carbonylmethyleneoxy | (and ml) are dissolved in methanol (10 ml) and heated in a hermetically closed tube at 100 phenyl|-5-fluoro-M4-(4-morpholinophenyl)-"C overnight. Then the reaction solution is diluted with an aqueous solution of 1M HCl (80 ml ). 2,4-pyrimidinediamine (K945360) The white precipitate is collected by filtration and washed with water, dried to form 3-(M- cyclopropylaminocarbonylmethyleneoxy)nitrobenzene, 1H' NAM? (SRCI3): 6 0.60 (t, 2H), 0, 85 (t, 2), 2.80 (tp, /- 3.6 Hz, 1H), 4.53 (5, 2H), 6.61 (g, IN, MH), 7.23 (dacha, 7 -06 and 2.7 and 8.4 gy, 1H), 7.49 (1-84 Hz, 10), 7.77 (6 2-24 Hz, IN), 7.90 (ad, 7 0.9 and 21 and VI

Gy, IN). 3-4M-cyclopropylaminocarbonylmethyleneoxy)nitrobenzene is reduced in the conditions of hydrogenolysis using 1095 RA-C in methanol at a pressure of 2.7 atm for 2 hours.

The catalyst is filtered. The filtrate is evaporated to form 344M-cyclopropylaminocarbonylmethyleneoxy aniline. 1N pit? (SS): 5 0.38 (t, 2H), 0.58 (t,

UA), 2.565 (t, 3- 3.6 Hz, 1), 4.19 (5, 28), 6.08 (t, 2H), 6.15 (4, U: 8.1 Hours, 1H) , 6.83 (b, 12 8.1

Hy, 1H)), 7.09 (g, IN, MH).

Similarly to the preparation of M4-(3,4-ethylenedioxyphenial)-5-fluoro-YH2-(3-tihydroxyphenyl)-2,4-pyrimidinediamine, M2-13-4(M-cyclopropylamino)carbonylmethyleneoxyphenyl|-5-fluoro-M4-( 4-morpholinophenia)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-0M-cyclopropylaminocarbonylmethyleneoxy aniline (200 me) and 2-chloro-5-fluoro-Ma-(4-morpholinophenyl)-4-pyrimidinamine (109 me), / H NMR (Sr): 6 0.55 (t, 2H), 0.81 (t, 2), 2.77 (t, 1: 3.6 Hz, 1H), 3.14 (i, 7-4 .8 Hz, 4), 3.87 (b 1--4.8 Hz, 4H), 4.50 (5, 2H), 6.52 (ava, 3- 0.9 and 2.4 and 8.1 Hz , 1H), 6.61 (bg, IN, MIV), 6.79 (4, 1: 2.4 Hz, 1), 6.92 (4.1- 90

Hy, 2H), 7.02 (di, 150.9 tav Hy, 18), 7.11 (be, 1H, MH), 7.18 y, 1-84 Hz, 1H), 7.50 (6 1 - total 7.48 (4.15 93 Hz, 2H), 7.92 (4.72 3.3 Go, 1Hu; IUE NMR (282 MHz, SOS); 5- 166.86; LC/MS: duration retention: 8.57 min.; purity: 885595; MS (m/z): 47953) (MN). 7.4.254 5-fluoro-M2-(3- Similar to the preparation of 4-(3,4-ethylenedioxyphenyl)-5-fluoro -M2-(3-thihydroxyphenyl)-2,4- methoxycarbonylmethyleneoxyphenyl)-Ма4- | pyrimidinediamine, 5-fluoro-M2-(3-methoxycarbonylmethyleneoxyphenyl)-М4А-(4-(4-morpholinophenyl)-2,4- morpholinophenyl) -2,4-pyrimidinediamine is obtained as a result of the reaction in methanol of 3-1(4-pyrimidinediamine (KU45361) morpholinophenyl)aminocarbonylmethyleneoxy aniline (200 mg) and 2-chloro-5-fluoro-M4-(4-morpholinophenyl)-4-pyrimidinamine (100 mg). YN NMR (SOSIZU: 5 3.15 (5, 1- 4.8 Gy, 4H), 3.80 (5, ZMI), 3.88 (1, 12: 4.8 Hz, 4NI ), 4.55 (5, 257), 6.55 (444, 4-0.9 and 2.7 and 8.1 i, 1H), 6.76 (be, 1H, MH), 6.94 ( y, 12 9.0 Hz, 2H), 7.06 (444, 7- 0.9 and 2.1 and 8.4 Hz, 18), 7.17 (228.4 Gu,

TNU 7.20 (Tu, IN, MN), 7.33 (0, 222.1 Gy, 18), 7.49 (4, 1 9.0 Hn, 2), 7.90 (4, 12 3, 3 Hz, IN); 19E YAM? (282 MHz, SOSIZu: 6 - 167.19; LC/MS: retention time: 9.32 min.; purity: 20252000 repairs 0000 s 7.4.255 M2-I3-(M- Analogous to the preparation of 3-0M-cyclopropylaminocarbonylmethyleneoxy)nitrobenzene , 3-He) cyclobutylamino)carbonylmethyleneoxy (M-cyclobutylaminocarbonylmethyleneoxy)nitrobenzene is obtained as a result of the reaction of 3-phenyl|).5-fluoro-M4-(4i-morpholinophenyl). (methoxycarbonylmethyleneoxy)nitrobenzene (2 g) and cyclobutylamine (1 g). 1H YAM? 2.4-pyrimidinedigmine (K945362) (SOSIZ): 5 1.69-1.80 (ha, 2H), 1.88-2.02 (t, 28), 2.34-2.44 St, 28), 4 .50 (t, 3-87 Hz, 18), 4.52 (5, 2H), 6.62 (g, IN, MH), 7.26 (444, 7- 0.9 and 3.6 and 9 ,0 Hz, 10), 7.50 (i, /- 85.4 Hz, 18), 7.80 (1.15 2.4 Hz, 1H), 7.91 (ad, 1- 0.9 and 2.1 and 8.4 Gy, 1). "with 34(M-cyclobutylaminocarbonylmethyleneoxy)nitrobenzene is reduced under the conditions of hydrogenolysis using 1099 RA-C in methanol at a pressure of 2.7 atm for 2 hours. Gee)

Zhatalist is filtered out. The filtrate is evaporated to form 34(M-cyclobutylaminocarbonylmethyleneoxy)anpiline. IN YAM (SOSIu: 6 1.60-1.70 Ot, 28), 1.80-1.93 (t, 2), 2.62 (t, NO), 4.31 (5, 2), 4 ... ), 6.85 (B, 1H, MH), 6.99 (5 12 8.1 Gy, TN).

Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-s pyrimidinediamine, M2-13-(M-cyclobutylamino)carbonylmethyleneoxyphenyl |-5-fluoro-M4 -(4-morpholinophenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-0M-(ee)cyclobutylaminocarbonylmethyleneoxy)aniline (200 mg) and 2-chloro-3-fluoro-Ma4-(4-morpholinophenyl)-4-pyrimidinamine (109 mg). 1H YAM? (SOCI3): 6 1.65-1.76 (t, 2Н), 1.84-1.97 (t, 280), 2.29-2.39 (t, 72Н)), 3.12 (1 . , 6.54 (4, 7- 0.9 and 2.4 and 8.4 Hz, 1NU), 6.68 (4.1- 8.1 Hz, 180), 6.65 (yes, 7- 3 ,0 and 5.4 gy, 1H), 6.90 (d, 1-90 ich, 2), 7.04 (04, 150.9 and 2.4 and 7.8 Go, IN), 7.16 (Bi, IN, MN), 7.17 0, 7-2 81 Bi, 1H), 7.40 (632 21 Hz, 1H), 7.48 (d, 159.0 Gy, 2H), 7.92 ( b 12 3.3 Go, 1); 19E NMR (282 MHz, SRS): 5 - 167.01; PH/MS: retention time: 9.54 - min.; purity: 88.8095; MS (m/z): 493.34 (MN). c 7.A4256 Ma cyclopropyl-M2-13-40M- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-х2-(3-hydroxyphenyl)-2,4-х cyclopropylamino)carbonylmethyleneoxy | of pyrimidinediamine, MA-cyclopropyl-M2-13-(M- and phenip|-5-fluoro-2,4-pyrimidinediamine cyclopropyzamino)carbonylmethyleneoxyphenyl |-5-fluoro-2,4-pyrimidinediamine is obtained in (K945363) as a result of the reaction of 3- (M-piclopropylaminocarbonylmethyleneoxy)aniline (200 mg) and 2-chloro-

M4-cyclopropyl-5-fluoro-4-pyrimidinamine (100 mg), 1n yam" (SRO); 6 0.55 (t, 2H), 0.72-0.79 (t, 4H), 0.89-0.96 (t, 2H), 2.72 (t, 7- 3.6 Gu, IN ), 3.03 (t, 2-36 Hz, IN), 4.50 (5, 2Н), 6.82 (d04d,1- 0.9 and 2.1 and 8.4 Hz, 11), 7 ... YAM? (282 MHz, CO); 5 - 164.97; РХ/MS: -y 42) 60 b5

17777101 duration of maintenance: 747 min; purity: 97285; MSM/in): 356.23 KhM. 7.4.257 Mm2-(I3-(M. Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-4(3-hydroxyphenyl)»-2,4-cyclobutylamino)carbonylmethyleneoxy pyrimidinediamine, M4-cyclopropyl- M2-134(M» phenyl-M4-cyclopropyl-5-fluoro-2,4-cyclobutylamino)carbonylmethyleneoxyphenyl|-5-fluoro-2,4-pyrimidinediamine is obtained in pyrimidinediamine (KO45364) as a result of the reaction of 3-(M-cyclobutylaminocarbonylmethyleneoxy)aniline (200 mg) and 2-chloro-

Ma-cyclopropyl-5-fluoro-4-pyrimidinamine (100 me). YIN YAM? (CO50B): 6 0.72 (t, 2H), 0.87-0.94 (t, 2), 1.68-1.79 (t, 2H), 197-241 (t, 2H), 2 ,23-2.353 (t, 2H), 2.99 (tp, 72 3.6

Gy, 1), 4.39 (t, 4- 8.1 Ge, IN), 4.48 (8, 7H), 6.77 (444, 1- 0.9 and 2.4 and 7.8 Gy , 183, 7.15 (da, 1: 0.0 and 1.8 and 8.1 Hz, 181), 7.29 (6.15: 8.E Hz, 18), 7.43 (4.321 Gu, 18). 72 min.; purity: 97.16595; MS (m/zu; 372.24 (MI). 7.A.258 Ma-cyclopropyl-5-fluoro-2-13-(4-3-(methoxycarbonylmethyleneoxy)nitrobenzene ( 2 g), 4-morpholinoanidine (1 g) and triethylamine morpholinophenyl)gaminocarbonylmethylene | (! ml) are dissolved in methanol (10 ml) and heated at 100 "C for 3 days. oxyphenyl|-2,4-pyrimidinediamine The reaction solution is diluted aqueous solution of 1M HCl (50 ml) and ethyl acetate (60 ml), (К945365) The white precipitate is collected by filtration and washed with water, dried to give 3-((4-morpholinophenyl)aminocarbonylmethyleneoxy|nitrobenzene. IN NMR (PM50-46): 5 3.24 (8,

AN), 3.85 (5, 4H)), 4.85 (5, 2H), 7.27 (t, 7H), 7.48 (ai, I» 2.4 and 8.4 Gy, IN) , 7.57-7.63 (t, ZN), 7.80-7.86 (t, 2H), 10.22 (ug, IN, MN). 3-Ca-morpholinophenyl)aminocarbonylmethyleneoxy |nitrobenzene is reduced under hydrogenolysis conditions using 1095 RA-C in methanol at a pressure of 2.7 atm for 2 hours.

R

The catalyst is filtered. The filtrate is evaporated to form 3-((4-morpholinophenyl)aminocarbonylmethyleneoxyaniline. /H NMR (CrCl3): 6 3.12 (0.72 4.8 g,

AN), 3.86 (53-48 Hz, 4NU, 4.54 (v, 2NI), 6.31-6.38 (t, ZN), 6.90 (4, 1 9.0 Gy, 2H) .

Similarly to the preparation of I44-43,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-tihydroxyphenyl)-2,4-pyrimidinediamine, M4-cyclopropyl-5-fluoro-42-(3-(4-morpholinophenyl)aminocarbonylmethypenoxyphenyl)- 2,4-pyrimidinediamine is obtained as a result of the reaction of 3-((4-morpholinophenyl)aminocarbonylmethyleneoxy aniline (200 mg) and 2-chloro-M4-cyclopropyl-5-fluoro-4-pyrimidinamine (100 mg). TN NMR (SOCI3): 5 0.64-0.69 (t, 2H), 0.88-0.96 (t, 2H), 2.87 (t, 1- 3.3 Hz, INU, 3.12 (6 24.8 Hz, "H), 3.86 (7:48 Gy,

AN), 4.61 (5, 2H), 6.60 (444, 12 0.9 and 2.4 and B.I Hz, 181), 6.90 (4, 2- 9.0 Gy, 2H), 7 ,11 (44, 1 1.8 and 8.1 Hn, IN), 7.23, 1-8.4 Go, 1H), 7.31 (5, 1H)), 7.46 (4.25.9, 0 Gy), 2H)), 7.75, 35 2.7 Hz, 7.79 (d, 35 3.3 Hz, 1H), V.16 (t, IN, MH; 19E NMR (282 MHz, SOSIZ ): 6 - 168.10; s pi! LC/MS: retention time: 9.03 min.; purity; 99.9795; MS (m/z): 479 (| 3. o 7.4.259 Ma-(3-chloro -4-hydroxy-5-methylphenyl)-5- |! Similar to the preparation of M4-(3,2-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-fluoro-M2-I3-(M - pyrimidinediamine, M4-(3-chloro-4-tihydroxy-5-methylphenyl)-5-fluoro-M2-13-0M-methylamino)carbonylmethyleneoxyphenyl|- | meevlamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine is obtained as a result of 2,a -pyrimidinediamine (H945366) reaction of 3-(methylaminocarbonylmethyleneoxy)aniline (200 mg) and 2-chloro-M4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-4-pyrimidinamine (100 mg). (0М50-й6): 6 2.17 (5,

ЗН), 2.62 (9, 1» 4.8 Gy, ЗН), 4.35 (5, 213), 6.56 (y, 12 8.4 Gy, 1Н)), 7.14 (t, 2H)), 7.29 (y, 1» 8.4 is e)

Zo Gu, 1), 741 b, 3- 3.3 Hn, IN, 7.54 (5, 2- 3.3 Hn, 1H), 7.94 (lh, INU, 8.12 (9, 7-42 Hz . ,56 min.; purity: 95.2795; MS (m/z): 432.15 (MN). 7.4.260 5-fluoro-M2-Y340M- Analogously to the preparation of 3-4(M-cyclopropylaminocarbonylmethyleneoxy)nitrobenzene, 5- c methylamino)carbonylmethyleneoxyphenyl)- | fluoro-M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl)-M4-(4-morpholinophenyl)-2,4-ma-(4-morpholinophenyl)-2,4-pyrimidinediamine is restrained as a result of the reaction of 5-fluoro-M2-( 3- sem pyrimidinediazmine (2945367) methoxycarbonylmethyleneoxyphenyl)-M4-(4-morpholinophenyl)-7,4-pyrimidinediamine (30 mg) and methylamine (30 mg). YIN YAM? (0OM5O-yv): 5 2.63 (y, 1- 4.5 Hz, ЗН), 3.040, 1-48 gy, (ee)

AN), 3.72 (5 12: 4.8 Hz, 4H), 4.32 (in, 2NI), 6.46 (44, 7» 7.8 Gv, 1H), 6.90 (9, 1 - 9.0 Hz, 2H), 7.08 (eV Hz, NU, 7.26 (y, 257.8 Gu, IN), 7.37 (5, 1), 7.60 (da, 15 3, 3 te 8.7 Hz, 241), 7.94 (ok, IN), 8.02 (4, 23.9 Hz, IN), 9.12 (be, IN), 9.15 (im, NU; 1?E NMR (282 MHz, OM5O-dv): 5 -167.17; LC/MS: retention time: 7.88 min.; purity: 99.4799; MS (m/z): 453.21 (Mn . " 7-4.261 5-fluoro-Ma-|4-(4- 14(4-nitrophenyl)piperazine (1 g), methylchloroformate (1 ml) and tristylamine (1 ml) methoxycarbonylpiperazino)phenyl|-M2- are obtained as a result reactions at room temperature in dichloromethane (10 ml) )

I3-(8- overnight. After extraction with ethyl acetate and water, organic var with methylamino)carbonylmethyleneoxyphenyl)- | evaporated and recrystallized from dichloromethane and hexanes to give 4-(4-2,4-pyrimyldiamine (К945368) methoxycarbonylpiperazino)nitrobenzene as a yellow solid. Then it is restored under the conditions of hydrogenolysis using 1095 RA-C in methanol at a pressure of 4 t and atm along the length of the stream. The catalyst is filtered. The filtrate is evaporated to give 4-(4-methoxycarbonylpiperazino)aniline. /H NMR (SOSIzu: 6 2.94 (i, 12 5.1 Gy, 15 4H), 3.59 0, 12 5.1 Hz, 45), 3.70 (5, ZNU, 6.62 (4 , 12: 8.7 Gy, 2H)), 6.78 (0.2-9.0 Hz, 28).

Similarly to the preparation of 2-chloro-M4-(3,4-ethylenedioxypheny)-5-fluoro-4-pyrimidinamine, (ee) 2-chloro-5-fluoro-M4-14-(4-methoxycarbonylpiperazino)phenyl|-4-pyrimidinamine obtained as a result of cutting 2,4-dichloro-5-fluoropyrimidine (300 mg, 1.8 mmol) and 4-(4-ko methoxycarbonylpiperazino)aniline (300 me). -y 42) 60 b5

Analogous to the preparation of M4-(3,4-ethyleneoxyphenyl)-5-fluoro-m2-3-tihydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-344-14-(4-methoxycarbonylpiperazino)phenyl|-M2-134( M» methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-(methylaminocarbonylmethyleneoxy aniline (150 mg) and 2-chloro-5-fluoro-M4-(4-(4-methoxycarbonylpiperazino)phenyl|-4-pyrimidinamine) (100 mg). IN YAM (OM5O-ar): 5 2.53 (a, 1--4.8 Gy, ZN), 3.04 0, 3- 5.1, NI), 3.50 (i, 1- 5 ,1 Gy, 4H), 3.61 (5, ЗН), 4.32 (5, 7H), 6.46 (а4,1- 2.1 and 7.8 Gy, 1H), 6.92 (d , 1-90 Gu, 2H), 7.08 (6, 7-51 Hz, IN), 7.24 (44, 120.9 and 8.4 Hz, 1H), 7.38 (0, 22 2, 1 Hp, 1H), 7.60 (9, 1- 9.0 Go, 2), 7.95 (0, 1- 3.9 Hz, 158), 8.02 (y, 4- 3.6 Ha , 1H), 9.13 (5, IN, MH), 9.17 (5, IN, MH); 12E NMR (282 MHz, OM5O-46): 5 - 164.93; LC/MS: retention time: 8.50 min.; purity: 944995; MS (m/z: 510.28 (Mn. 74262 M2-14-(/M-acetyl-M-methylamino)phenyl|- Analogous to the preparation of 4-(4-methoxycarboylpiperazino)nitrobenzene , M-acetyl-M-

M4-cyclopropyl-5-fluoro-2,4-methyl-4-nitroaniline is obtained as a result of the reaction of M-methyl-4-nitroaniline (and d) and pyrimidinediamine (K945369) with acetyl chloride (1 ml). IN NMR (SOSIz): 5 2.03 (v, ZN), 3.35 (5, ZNU, 7.39 (4, 1-9.0 Ty, 2H), 8.28 (a, 1-9.0 Hz , 2H).

M-acetyl-M-methyl-d-nitroaniline is reduced under conditions of hydrogenolysis using 1095 pRa-C in methanol under a pressure of 4 atm for 1 hour. The catalyst is filtered.

The filtrate is evaporated to give 4-(M-acetyl-M-methylamino)aniline. etc. YAM" (SOSIZU: 6 1.80 (in, ZNU, 3.14 (in, ZIN), 6.63 (4, 7-8.1 Hn, 2H), 6.88 (y, 3-2 8.7 Hz, 2H).

Similarly to the preparation of M4A-(3,4-styrenelioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(4-(M-acetyl-M-methylamino)phenyl|-Ma4-cyclopropyl -5-fluoro-74" pyrimidinediamine is restrained as a result of the reaction of 4-(M-acetyl-M-methylamino)aniline (200 mg) and 2-chloro-M4-piclopropyl-5-fluoro-4-pyrimidinamine (100 mg). IN YM?srsesi6 0.67 (tp, 2H), 0.83-0.97 (t, 2NI), 1.88 (5, ZN), 2.85 (t, 7: 3.3 Gy, 18), 3.24 (5, ZN), 5.31 (w, 1NU, 7.10 (4, 3-2 8.7 Go, 28), 7.36 (Bk, 18), 7.73 (4, 15 8.7 Go, 2), 7.78 (y, 12 3.3 Hz, IN; 19E

NMR (282 MGy, SOSI z): 5 - 168.13; LC/MS: retention time: 6.65 min.; purity: 10095; MS (m/z: 316.22 (MN). 7.A.263 M2-(444-acetylpiperazino)phenyl-M4- Analogously to the preparation of 4-(4-methoxycarbonylpiperazino)nitrobenzene, 4-(4- cyclopronyl-5-fluoro -2,4- acetylpiperazino)nitrobenzene is obtained as a result of the reaction of 1-44-nitrophenyl)ptiperazine pyrimidinediamine (2945370) (1 g) and acetyl chloride (1 ml). YV NMR (SOSIZ); 5 2.16 (in, ZN), 3.46 (be, 4H), 3.68 (bg, 2), 3.80 (bg, 2H), 6.84 (0, 1: 9.6 Hz, 2H), 8.15 (d, 15 9.6 Hz, 28). 4-(4 acetylpiperazino)nitrobenzene is reduced under the conditions of hydrogenolysis using a temperature of 1095 pRa-C in methanol under a pressure of 4 atm for 1 hour. The catalyst is filtered. si - -sch -

The filtrate is evaporated to form 4-(4-acetylpiperazino)aniline. IN NMR wasa: 6 Ge) 2.10 (5, ZNU, 2.97 (p, 3» 4.8 Gy, 4H), 3.58 (I, 1» 4.8 Gu, 2H), 3.72 (I , 1- 5.1 Gy, 2H), 6.64 (8, 35 8.7 Gy, 215, 6.78 (4, U 8.4 Hn, 2H).

Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenia)-2,4-pyrimidinedigamine, M2-14-(4-apetylthiperazino)phenyl|-Ma-cyclopropyl-5-fluoro- 2,4-pyrimidineligmine is obtained as a result of the reaction of 4-x4-acetylpyrrazno)aniline (200 mg) with 2-chloro-M4-cyclopropyl-5-fluoro-4-pyrimidinamine (100 mg). YIN YAM? (SOSI3): 6 9.66 (t, 28), 0.00 (t, ZNU, 2.14 (in, ZNU), 2.84 (q, 1-- 3.3 Gy, 18), 3, 10 (p, 22 5.4 Hz, 4H)), 3.62 (i, 72 b 5.1 Hz, 2H), 3.77 (5 2- 5.1 Hz, 2H)), 5.33 ( Bt, IN), 6.90 (4, 1- 9.0 Hz, 2H), 7.43 (bg, 18), 7.57 (4.159, hz, ZNU, 7.71 (8, 1- 3, 6 Hn, 1H); 192 NMR (282 MHz, SOSIZ): 5 - 168.95; LC/MS: retention time: 6.79 min.; purity: 93.1495; MIS (m/z): 371.50 (MH ). "-- 7.4.264 ma-piclopropyl-5-fluoro-M2-(4-(4- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2, 4- se methoxycarbonylpiperazino)phenyl)-2,4-pyrimidinediamine, M4-cyclopropyl-5-fluoro-M2-|4-(4-methoxycarbonylpiperazino)phenyl|- pyrimidinediamine (K945371) 2,4-pyrimidinedismine is obtained as a result of the reaction of 4- (4-methoxycarbonylpiperazino)aniline (200 mg) and 2-chloro-M4A-piclopropyl-5-fluoro-4-he)pyrimidinamine (100 mg). 1NMR (SOCI3U: 5 0.65 (t, 2H), 0.88 (t, 2H), 2.84 (t, 15 3.3

Gy, 19), 3.07 (i, 22 4.8 Go, 4H), 3.63 (, 12: 5.1 Gy, ZNU, 3.73 (5, ZNU, 5.29 (g, NN) , 6.90 (4, 1- 9.0 Hz, 2H), 7.38 (bg, 1), 7.56 (4, 2: 8.7 Gu, 2NU, 7.71 (4, 1- 3 ,6 Gy, 1H)3; 19E YAM (282

MG, SOSIz): 8 - 169413; RHLMS: retention time: 7.86 min.; purity: 91.6395; MS " (m/z): 387.20 (Mn. 74.265) M4-cyclopropyl-5-fluoro-M2-Y34(M-) similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3Z- hydroxyphenyl)-2,4- shsh methylamino)carbonylmethyleneoxyphenyl)- | pyrimidinediamine, M4-cycloprodyl-5-fluoro-M2-(3-(Msh-c 2,A-pyrimidinediamine (К945372) methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3"(methylaminocarbonylmethyleneoxy aniline (200 mg) and 2-Chloro-M4-piclopropyl-5-c"fluoro-4-pyrimidinamine (100 mg). 1NMR (SOSIV): δ 0.66 (t, 2NI), 0.91 (t, 2H) . and 2.4 and 7.8 Hz, IN), 6.60 (ve, 1H), 7.13 (444, 12 1.2 and 8.1 Gy, 1NI), 7.20 (3, 72 8, 1 Hz, 18), 7.31 (g, IN), 7.61 (.1- 415 2, Hn, 18), 7.80 (4, 1- 3.6 Gu, 1NU; 1I9E NMR (282 MHz , SOSIZ); 5 - 168.24; LC/MS: retention time: 6.78 min.; purity: 89.6595; MS (m/z): 332.19 (MN). so 7.A.266 Mdecyclopropyl - 5-fluoro-M4»|44(4- Similar to the preparation of Ma4-(3,4-styrenedioxyphenyl)-5-fluoro-12-(3-hydroxyphenyl)-2,4- methoxycarbonylpiperazino)phenyl|-2,4- pyrimidinediamine , M2-cyclopropyl-5-fluoro-M4-14-(4-methoxycarbonylpiperazino)phenyl|-2,4- co pyrimidinediamine (K945373) pyrimidinediami n is obtained as a result of the reaction of cyclopropylamine (150 mg) and 2-chloro-5- (Ce) 42) ko 60 b5 fluoro-M4-144(4-methoxycarbonylpiperazino)phenyl)-4-pyrimidinamine (100 mg). YIN YAM? (SOSIZ); 6 0.60 (t, 2H), 0.81 (t, 2H), 2.72 (t, 7- 3.3 Gy, 18), 3.13 (i, 7: 5.1 Gy, 4H) , 3.64 (I, 1-51 Hz, 4), 3.73 (8, ZN), 6.924, 3-90 Gu, 2H), 7.63 (0, 1-90 Hz, 28, 7.76 (y, 1-30 Hz, 1H); 192 NMR (282 MGa, SOCI3): 6 - 168.70; LC/MS: retention time: 7.59 min., purity: 92.0795; MS (m/z ); 387.27 (МН. 7.426067 М2-cyclobutyl-5-fluoro-М4-(4-(4- Analogous to the preparation of 1М4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-(3-hydroxyphenyl)-2 ,4-methoxycarbonylpiperazino)phenyl|-2,4-|pyrimidinediamine, M2-cyclobutyl-5-fluoro-M4-(4-(4-methoxycarbonylpiperazino)phenyl)- pyrimidinediamine (5945374) 2,4-pyrimidinediamine is obtained as a result of the reaction of cyclobutylamine (150 mg) and 2-chloro-5-fluoro-Ma4-|4-(4-methoxycarbonylpyrazino)phenyl|-4-pyrimidinamine (100 mg). NMR (SOSIZ); 6 1.68-1.78 (t, 2), 1.82-1.92 (t, 2NI), 2.33-2.43 (t, 28), 3.12 (6. 2- 5.1 Hz, 48), 3, 64 (5.7 5.1 Gy, AN), 3.74 (5, ZN), 4.31 (t, 1-7.8 Hn, IN), 5.42 (it, IN), 6.69 (w, IN), 6.93 70 (4.1-9.3 Hz, 2H), 7.53 (4, 22:9.0 Hz, 2H), 7.76 (4, 1: 3.6 Il 1H); 19E NMR (282 MG,

SOSI3u: 5 - 170.64; LC/MS: retention time: 8.34 min.; purity: 82.5395; MS (m/z); 401.28 (МН. 7.4.268 m4-I4-(M-acetyl-M-methylamino)phenyl|- Analogously to the preparation of 2-chloro-Ma-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine,

TM2-cyclopropyl-5-fluoro-2,4-Ma-(4-0M-acetyl-M-methylamino)phenia|-2-chloro-5-fluoro-4-pyrimidinamine is obtained in pyrimidinediamine (H945375) as a result of the reaction 2,4 -dichloro-5-fluoropyrimidic acid (300 mg, 1.8 mmol) and 4-(M-acetyl-M-methylamino)aniline (300 mg).

Similarly to the preparation of M4-4(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, M4-14-(h-acetyl-h-methylamino)phenyl-M2-cyclopropyl- 5-fluoro-7,4-pyrimidinediamine is obtained as a result of the reaction of cyclopropylamine (150 mg) and M4-H4-(M-acetyl-M-methylamino)phenyl-2-chloro-5-fluoro-4-pyrimidinamine (100 mg). INn'yaYAME (SOSIZ): 6 0.66 (t, 2H), 0.85 (t, 2H), 1.90 (v, ЗН), 2.74 (to, 1H)), 3.27 (5 , ZNU, 7.22 (4, 2Н), 7.84 (0, ZNU; RH/MS: retention time: 5.91 min.; purity: 79.7400; MS (m/z): 316.23 (MN. 7.4.269 M2,Ma-bis(cyclopropyl)-5-fluoro-2,4- During the preparation of M4-(4-(M-acetyl-M-methylamino)phenyl|-K2-cyclopropyl-5-fluoro-2, 4-pyrimidinediamine (8945376) of pyrimidinediamine, the formation of 142, M4-bis(cyclopropyl)-5-fluoro-2,4" pyrimidinediamine is observed as a side product. IN YAM" (SOS): 5 0.49-0.59 (t, 4H), 0.73-0.84 (t, 4H), 2.67-2.79 (t, 2H)), 5.04 (Be, 1H), 5.14 (g, 1H), 7, 73 (4, 1: 3.6 Hu, NU; I9E NMR (282

MHz, SOSIZ): 8- 171.76; LC/MS: retention time: 2.63 min.; purity; 96.9195; MS (m/z): 209.16 (MN). -ЗZZ--- - - 5 / -- - - O« - -- -- - - - 4-- - -Ч - Я - - с 7.4.270 Ma-|4-(M-acetyl-M-methylamino )phenyal|- Similar to the preparation of 144-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-5-fluoro-M2-(3-M-pyrimidinediamine, M4-14-( M-acetyl-M-methylamino)phenyl|-5-fluoro-M2-13-(M-He)methylamino)carbonylmethyleneoxyphenyl|- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinedismine is obtained as a result of the reaction of 2,A-pyrimidinediamine (KU45377) with 3-(-M-methylamino)carbonylmethyleneoxyaniline (150 mg) and M4-H44(M-acetyl-M-

And methylamino)phenyl-2-chloro-5-fluoro-4-pyrimidinamine (100 me), 1H NAM? (SOSIz): 6 1.89 (5,

ZNU, 2.89 (a, 1- 5.1 Gy, ZN), 3.26 (5, ZNU, 4.47 (5, 28), 6.59 (44, 3- 2.4 and 8.1 Hn, 1), 7.12-7.24 (t, 4H), 7.30 (g, 19), 7.350, 21-2.1 Hz, 1H), 7.70(d, 4- 8.4 Hn, 2NU, 8.01 (0, 12 3.0 Hz, "se nu; Y9e NMR (282 MGy, SOS): 8 - 165.91; LC/MS: retention time: 7.94 min.; purity: 89, 7895; MS (mizu: 439.50 (MN). b

CJSC MmaMa4-bis(3- During the synthesis of M4-14-0Ch-acetyl-M-methylamino)phenyl-5-fluoro-M2-(3-(M- methylaminocarbonylmethyleneoxyphenyl)- | methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine , observe the formation of h-5-fluoro-2,4-pyrimidinediamine (K945378) M2,MA-bis3-methylaminocarbonylmethyleneoxyphenyl)-5-fluoro-2,4-pyrimidinediamine as a side product. 1 Yam? (SOSI3u: 6 2.87 (4, 12 4.8 Gy, ZN), 2.90 (y, 1- 4.8 Gu, ZN), s 4.46 (5, 2H), 4.54 (5 , 2H), 6.53 (ai, 1- 0.9 and 2.4 and 7.8 Hz, 2NI), 6.69 (444, 1- 0.9 and 2.7 and 8.1

Tu, 2H), 6.82 (ai, ze 1.2 and 7.8 Hz, 1H), 6.92 (a, 4-2 3.0 Hz, TN), 7.19-7.30 (t, Z ), 7.65 (i, 1- 21 Ha, 1H), 8.00 (4, 1- 3.3 Gl, 1NU, 8.04 (back, 1, 8.12 (i, 72 2.1 Gu , 1NU; 19E YAM (282 MHz, (ge)

SOSI3): 6-167.11; LC/MS: retention time: 7.93 min.; purity: 96.85; MS (m/z); 455.50 (MH). 7.4.272 Mma-IA-(M-acetyl-M-methylamino)phenyl)- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-

M2-cyclobutyl-5-fluoro-2,4-pyrimidinediamine, M4-144(M-acetyl-M-methylamino)phenyl|-M2-cyclobutyl-5-fluoro-2,4- " pyrimidinediamine (5945379) trimidinediamine is obtained as a result reaction of cyclobutylamine (150 mg) and M4-Y44(M-zcetyl-M-methylamino)phenyl|-2-chloro-5-fluoro-4-pyrimidinamine (100 ml). !N' YAM? (SOSI3); w-in 6 1.70-1.97 (iz, AN), 1.89 (z, ЗН), 2.36-2.45 (t, 2Н), 3.26 (5, ЗН), 4, 33 (t, 1: 7.8 Hz, 18), 5.13 s (9.12 7.2 Ha, 1), 6.87 (rt, 18), 7.160, 7: 8.7 Gy, 2H), 7 .73 (d, 19.0 Gy, 2H)), 7.86 (d, 1- 3.6 and go, 1); 192 NMR. (282 MHn, SOSI3): 5 -170.61; RH/MS. duration of retention: 7.03 min.; and» purity: 93.0492: MS (m/zu: 330.16 (MIN). 7.4.273 Ma Ma-bis(cyclobutyl)-5-fluoro-2,4- Nid preparation time M4-(4-(М -acetyl-M-methylamino)phenyl|-M2-cyclobutyl-5-fluoro-2,4-pyrimidinediamine (K945380) of pyrimidinediamine, the formation of M2.M4-bis(cyclobutyl)-5-fluoro-2,4-pyrimidinediamine is observed as a by-product of the product.

Go! (t, ZNU, 4.31 (tp, 1- 7.8 Ha, IN), 4.50 (t, 12 7.8 Gy, IN), 4.99 (be, 2H), 7.63 (4 , 1-3.6 Hz,

IN); 19E NMR (282 MHz, SOCI3): 6 - 172.68; LC/MS: retention time: 8.35 min.; ko -y (Se) 42) ko 60 b5

01111100 fchietiut obov Mosmach atomicnu, 7.427174 ma-(4-(4-acevylayperazino)phenylI-M2- Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, cyclopropyl-z-fluoro -2,4- 1m4-14-(4-acetylpiperazino)phenyl|-2-chloro-5-fluoro-4-pyrimidinamine is obtained in pyrimidinediamine (K945381) as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine (300 mg, 1 .8 mmol) and 44(4-anethylpiperazino)aniline (300 mg).

Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinedimine, M4-14-(4-acetylpiperazivo)phenyl|-M2-cyclopropyl-5-fluoro- 7,4-pyrimidinediamine is obtained as a result of the reaction of cycloprolylamine (150 mg) and Ma4-(4-(4-acetylpiperazino)phenyl|-2-chloro-5-fluoro-4-pyrimidinamine (100 me). 0.75 (t, 2H)), 0.84 (t, 2H), 2.18 (5, ЗН), 2.76 (t, 32 3.3 Hz, 1H), 3.23 (p, 1 - 5.4 Hz, 4), 3.68 (3-5, Ho, 2H)U, 3.82 (5.42 5.1 Ho, 2H)), 6.98 (4, 7- 9.0 Gy, 2H), 7.45 (9, 1: 3.0 Hz, 10), 7.65 (3-5 Hz, 1), 7.71 (463-950 Hz, 2), 970 (t, INU; I9E NMR (282 MHz, SOS): 5 - 170 166.00; LC/MS: retention time: 6.50 min.; purity: 93.5695; MS (m/z): 371.24 (MN). 74275 ma -(14-(4-acetylpiperazino)phenyl|i-M2- Similar to the preparation of M4A-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-cyclobutyl-5-fluoro-2 ,4-pyrimidinediamine|pyrimidinediamine, M4-(4-(4-acetylpiperazino)phenyl|-M2-cyclobutyl-5-fluoro-2,4- (K945382) pyrimidinediamine is obtained as a result of the reaction cyclobutylamine (150 mg) and M4-(4-(4-acetypliperazino)phenyl|-2-chloro-5-fluoro-4-pyrimidinamine (100 mg). NMR (SOS): 6 1.59-1.88 (t, 2H), 2.07-2.37 (tp, 414), 2.18 (v, ZN), 3.25 (p, 2 - 5.4 Gy, 4NI), 3.68 (1.1- 5.1 Hz, 2H)U, 3.83 (512 5.1 Gm, 2H), 4.27 (t, 12 7.2 Hz , 1H), 6.99 (4, 3-93 Gy, 2H), 7.40 (g, 19), 7.55 (4, 1 9.0 Gy, ZN), 7.62 (4, 3- 5.1 Gy, 1), 9.69 (Bk, 1H); 19E NMR (282 MHz, SOSIZ): b - 166.57; LC/MS: retention time: 7.23 min.; purity: 89.0495; MS (m/z): 385.25 nn (M). In 7.4.275 M2-(4-(M-acetyl-M-methylaminophenyl|- Analogously to the preparation of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-pyrimidinamine,

Mea-cyclobutyl-5-fluoro-2,4-2-chloro-Mea-cyclobutyl-5-fluoro-4-pyrimidinamine is obtained as a result of the reaction at room temperature of pyrimidinediamine (5945383) with 2,4-dichloro-5-fluoropyrimiline (400 mg, 2 .4 mmol) and cyclobutylamine (200 mg).

Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl. 3-fluoro-M2-(3-hydroxyphenyl)-2,4- pyrimidineliamine, M2-14-(M-adethyl-M-methylamino)phenyl!-M4-cyclobutyl-5 -fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 4-(M-acetylm-methylamino)aniline (100 mg) and 2-chloro-M4-cyclobutyl-5-fluoro-4-pyrimidinamine (100 mg), 1H nNMR ( SOSIZ3): 5 1.75-7.02 (t, 49), 1.88 (5, ZN), 2.41-7.51 (t, 2H), 3.24 (in, ZNU, 4.53 (t, 1- 7.8 Hz, IN), 5.17 (a, 6.3 Hz, 1Н), 7.06 (bu, 1Н), 7.19 (4, le 8.7 Hz, 7Н) , 7.63 (4, /- 9.0 Hz, 2), 7.78 (d,3- 3.3

Hz, IN); I9E NMR (252 MHz, SOS): 5 - 168.52; PH/MS: retention time: 7.41 min.; Ha

Z Ot 2 1 OO OPO 1 pru oizea men zv mnu, o 74277 Cistrane-MMA-14-44-Stret- Hydrochloride of cis/trans-4-aminocyclohexanol (10 g), di-tert-butyl dicarbonate (20 g) and butoxycarbonylamino )cyclohexyloxy | sodium bicarbonate (20 g) is dissolved in THF (50 ml) and water (50 ml). The reaction solution of 3-chlorophenyl|-5-fluoro-1M2-H3-40M- is stirred at room temperature overnight. The solution is extracted with methylamino)carbonylmethyleneoxyphenyl)- | ethyl acetate (100 ml) and the organic layer is evaporated to give 4-tert-2,4-pyrimidinediamine (K945384) butoxycarbonylamino-cyclohexanol.

Cis/trane-4-tert-butoxycarbonylaminocyclohexanol (10 g) was dissolved in dichloromethane (Ce) (100 ml). Add p-toluenesulfonyl chloride (10 g), OMAR (5 g) and triethylamine (10 ml) to the solution and stir at room temperature overnight, (e")

The reaction mixture is washed with an aqueous solution of IM NH (3 x 100 ml), dried and evaporated to give cis/trans-O-p-toluenesulfonyl-4-tert-butoxycarbonylaminocyclohexanope. or

Cis/trans-O-p-toluenesulfonyl-4-tert-butoxycarbonylaminocyclohexanoyl (10 g), 2-chloro-4-nitrophenol (10 g) and potassium carbonate (10 g) are triturated at 60 °C in DMF (50 ml) on Ha! for 4 hours. The solution was diluted with ethyl acetate (100 ml) and washed with water (3 x 100 ml). The organic layer is dried, evaporated to form 4-(44(tert-

C5-butoxycarbonylamino)cyclohexyloxy|-3-chloronitrobenzene. It is restored under the conditions of hydrogenolysis using 1095 Ra-C in methanol under a pressure of 4 ztm during | hours

The catalyst is filtered off - the filtrate is evaporated to form 4-(4-tert-butoxycarbonylamino)diclohexyloxy|-3-chloroaniline.

Similarly to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, ma-(4-H4-(tert-butoxycarbonylamino)cyclohexyloxy|-3-chlorophenyl|-2-chloro-5- fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-14-(tert-butoxycarbonylamino)alkylhexyloxy|-3-chloroaniline.

Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-7,4-)pyrimylindiamine, M4-(4-I4-(tert-butoxycarbonylamino)zpiclohexyloxy|-3-chlorophenia| -5-s fluoro-M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-(methylaminocarbonylmethyleneoxy)aniline and M4-14-|4(tert» in!z» butoxycarbonylamino)cyclohexyloxy |-3-chlorophenyl|-2-chloro-5-fluoro-4-pyrimidinamine. n РХ/MS: retention time: 12.83 min.; purity: 96.2095; MS (m/z): 615.32 (M). 7A2B M2-(14-(4-acetylpiperazino)phenyl-M4- Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-cyclobutyl-5-fluoro-2 ,4-pyrimidinediamine|pyrimidinediamine, 142-|44(4-acetylpiperazino)phenyl|-M4-cyclobutyl-5-fluoro-2,4- (K945385) pyrimidinediamine is obtained as a result of the reaction of 4-(4-acetylpiperazinosaniline (100 mg) ( ee) and 2-chloro-M4-cyclobutyl-5-fluoro-4-pyrimidinamine (100 mg). In NMR (SOS): 6 1.72- 1.99 (t, 4H), 2.13 (8, ЗН ), 2.39-2.49 (t, 20), 3.09 (in, 7: 5.1 Gu, ZNU, 3.61 (i, 72 8.1 Gn, 28), t sho | 3u77 ( 6125, Hz, 2H), 4.51 (t, 72 7.8 Hn, IN), 5.10 (8.2- 6.9 Gy, EN), 6.85 (Bk, 18), 6.90 (y , -y 42) 60 b5

19.0 Hz, 2H), 7.46 (6.1 9.0 Gy, 2H)), 7.73 (8.1-3.3 Gy, 1H)); IUE NMR (282 MHz, SOSIZH: 6 - 170.01; LC/MS: retention time: 7.26 min.; purity: 90.4995; MS (m/z): 385.25 (MN. 7.4.279 Ma -cyclobutyl-5-fluoro-M2-|4-4- Similar to the preparation of M4-(3,4-ethylenelioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- methoxycarbonylpiperazine)phenyl|-2,4 -| pyrimidinediamine, M4-cyclobutyl»5-fluoro-M2-(4-(4-methoxycarbonylpiperazino)phenyl|» pyrimidinediamine (К945386) 2,4-pyrimidinediamine is obtained as a result of the reaction of 4-(4-methoxycarbonylpiperazino)aniline (100 mg) and 2-chloro-M4A-cyclobutyl-5-fluoro-4-pyrimidinamine (100 mg). 1H NAM" (SOSISU: 6 1.72-1.85 (t, 2), 1.88-1.99 (p , 2H), 2.38- 2.48 (t, 2H), 3.06 (b, 7- 5.1 Hz, 4H), 3.62 (i, 72 5.1 Hz, 4), 3, 72 (5, ZE), 4.51 (t, 1- 7.8 Gu, 1H), 5.09 (y, 7- 6.3 Hz, 1), 6.90 (d, 7- 9.0 Hz, 2H), 6.91 (g, 1, 7.45 (y, 2- 9.0 Hz, 2H), 7.73 (a, 153.3 Hz, 18); 192 YAME (282 MGy, SOSIZ ); 6 - 170.12; LC/MS: retention time: 706 8.48 min.; purity: 94.1895; MS (m/z3: 401.21 (MH). 7.4.280 Ma-cyclobutyl-5- fluoro-M2-13-(M- Prepared similarly annu M4-(3,4-ethylenedioxyphenia)-5-fluoro-M2-(3-tihydroxyphenyl)-2,4-methylamino)carbonylmethyleneoxyphenyl)- | pyrimidinediamine, M4-cyclobutyl-5-fluoro-1х2-13-(M-2,4-pyrimidinidiamine (К945387) methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-(methylaminocarbonylmethyleneoxy aniline (100 mg) and 2 -chloro-M4-cyclobutyl-5-fluoro-4-pyrimidinamine (100 me). other NAM (0M50-a6): 5 1.71 st, 2H), 2.14 (t, 2H), 2.25 (t , 2H), 2.64 (8, 1-4.2 Hz, ZN), 4.45 (5, 2H), 4.51 (t, 1H), 6.70 (4 3-81 Go, NO) , 7.13 (4, 1-81 Hz, Nu, 7.26 (01-81 Hn, 18), 7.32 (1, EN), 8.03 (4.15 4.5 Hu, 1H)) , 8.10 (9, 75 5.4 Hz, 18), 9.04 (g, IN), 10.18 (lk, 1H); 19E YAM (282 MGy, OM5O-ab): 5 - 163.00; RHUMS: duration of retention: 7.50 min.; purity: 95.4795; MS (m/z): 346.20 (m ) 7.4.281 M2-I34(M- Analogous to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- cyclobutylamino)carbonylmethyleneoxy pyrimidinediamine, M2-I3-(M-cyclobutylamino)carbonylmethyleneoxyphenyl|-5-fluoro-MA-(2H-phenyl|-5-fluoro-M4-2H-3-oxo-4H-5-3-oxo-4H -5-pyrido(1,4oxazin-b-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of pyridi 1,4)oxazin-b-yl)-2,4- 3-(M-cyclobutylaminocarbonylmethyleneoxy aniline (100 mg) and 2-chloro-5-fluoro-M4-42H-3-pyrimidinediamine (K945389) oxo-4H-5-pyridi1,)oxazin-b-yl)-4-pyrimidinamine (50 mg). IN NMR (OM5O-4r): 8 1.53-1.65 (t, 2H), 1.90-2.03 (t, 7), 2.07-2.17 (t, 213), 4, 25 (d, 2-8.1 Hz, IN), 4.32 (z, 2H), 4.61 (5.2H), 6.46 (ad, 12 1.8 and 8.1 Hz, 1H) , 7.10 (5.7: 8.1 Hz 1), 7.23 (ad, 1-0.9ta84 gy, 1), 7.38 (t, 2H), 7.60 (0.41: 8.7 Hn, 1H)U, 8.13 (y, - 3.6 Hz, 1H), 8.22 (90, 1-81 Hz, IN), 9.23 (5,

TEO), 9.26 (5, IN), 1.12 (5, INU; 192 NMR (282 MHz, OM5O-0r): 6 - 163.26; LC/MS: retention time: 9.98 min.; purity: 92.2195; MS (m/z): 480.25 (MN). ch 7.4.282 M2-I3-(M. Analogously to the preparation of IM4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-( 3-hydroxyphenyl)-2,4-cyclopropylamino)carbonylmethyleneoxy|pyrimidinediamine, M2-|3-0M-cpcyclopropylamino)carbonylmethyleneoxyphenyl|-5-fluoro-M4- He) phenyl)-5-fluoro-M4-02H-3-oxo- 4H-5-(2H-3-oxo-4H-5-pyridi 1,4oxazin-6-yl)-2,4-pyrimidinediamine is obtained as a result of pyridi 1,4)oxazin-b-yl)-2,4- reaction of 3-(M-cyclopropylaminocarbonylmethyleneoxy)aniline (100 me) and 2-chloro-5-fluoropyrimidinediamine (K945390) MAN oxo-4H-5-pyridine and oxazin-b-yl)-4-pyrimidinamine (50 mg). !H NMR (OM5O0- dv: 6 0.47 st, 2H), 0.61 (t, 2), 2.66 (t, 72: 3.6 Hz, 1H), 4.32 (v, 2H), 4 .52 (5, 2H), 6.44 (yes,

And 2.4 and 7.5 Hz, 1), 7.09 (5.22: 8.1 Hz, 1), 7.22 (yes, 1- 0.9 and 8.1 Hz, TA), 7.37 (t, 7H), (Te) 7.590, p: 8.4 Hz, 1H), 8.05 (0.3- 4.5 Hz, 1H), 8.13 (а, 7- 3.6 Hz, 1NO), 9.22 (in, 1H), 9.26 (in,

TNu 11.12 (5.1Nu; ISE NMR (282 MHz, OM50-46): 6 - 163.27; LC/MS: duration of F retention: 8.89 min.; purity: 83.29; MS (m/ z): 466.24 (МН. 74283 M2-(444 acetylpiperazino)phenyl|-5- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphanyl)-2,4-h -: fluoro-ma-(2H-3-oxo-4H-5-pyrimidinediamine, M2-(4-44-apetylpiperazino)phenyl |-5-fluoro-M442H.3-oxo-4H.-5-pyrid| 1, Oxazin-b-yl)-2,4-pyridi!oxazin-b-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 4-(4-pyrimidinediamine (945391) acetylpiperazino)aniline (100 mg) and 2-chloro- 5-fluoro-M4A42 H-Z-oxo-4H-5-sempyrido(1,5-oxazin-6-yl)-4-pyrimidinamine (50 mg). 1H NAM (OM50-y6): 5 2.02 (5, ZN), 2.961.1- 5.1 Gy, 2H), 3.02 (y, 2- 5.1 Gy, 2H), 3.55 (g, YAN), 4.62 (5, 2H), 6 .84 (4.1-9.0 Hz, (ee) 2H), 7.36 (0.7: V Hz, 1), 7.48 (0.2-90 Hz, 2H)), 7.57 (a, 7-8.7 Hz, 18), 8.0744.3-3.6 Hz, 1TNU, 9.01 (c, 1H), 9.13 (c, NU, 11.14 (z, IN 19E NMR (282 MHz, OM5O-th): 8 - 164.84;

LC/MS: retention time: 7.29 min.; purity: 88.4690; MS (m/z): 479.27 (MN). 7A28A 5-fluoro-M2-1444. Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-" methoxycarbonylpiperazino)phenyl|-M4-pyrimidinediamine, 5-fluoro-M2-14-(4-methoxycarbonylpiperazino )phenyl-M4-4(2H-3-oxo-4H- (2H-3-oxo-4H-5-pyridi I Yaoxazin-6-5-pyridi 1,4)oxazin-b-yl)-2,4- pyrimidinediamine is obtained as a result of the reaction of 4-44-yl)-2,4-pyrimidinediamine (K945392) methoxycarbenylliperazino)aniline (100 me) and 2-chloro-5-fluoro-M4-(2H-3-oxo-4H-5- shsh with pyridinium 1,4|oxazin-b-yl)-4-pyrimidinamine (50 mg). YIN YAM? (0500-46): 5 2.98 (B, 15 5.1

Ty, 41), 3.48 (I, 3- 5.1 Hz, 4H), 3.50 (5, ЗН), 4.52 (5, 2H), 6.83 (y, 7- 9.3 Gy, 2H), 7.36 (d, 3-p 8.4 Gy, 1), 7.47 (j, 7 9.0 Gy, 2). 7.56 (a, y- 8.4 Hz, 1H), 8.06 (0, 1- 3.6 Hu, 1H), 9.01 (5, "» 1.913 (5, NU; /9E NMR ( 282 MHz, РМ5О-00): 6 - 164.84; LC/MS: retention time: 8.61 min.; purity: 83.0005; MS (m/z): 495.25 (MN). 7.4.285 M4-cyclobutyl-M2-(3- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- cyclopropylaminocarbonylmethyleneoxy pyrimidinediamine, M4-cyclobutynl- M2-(3-0 - o phenyl)-5-fluoro-2,4-pyrimidinediamine cyclopropylamino)carbonylmethyleneoxyphenyl|-5-fluoro-2,4-pyrimidinediamine is obtained in (K945393) as a result of the reaction of 3-M-cyclopropylaminocarbonylmethyleneoxy aniline (100 mg) and 2-chloro» ko -y (Se) 42) ko 60 b5

Na-cyclobutyl-5-fluoro-4-pyrimidinamine (50 mg). IN NMR (SOS): δ 0.58 (pa, 2H)), 0.80-0.90 (tp, 2H)), 1.78-1.89 (tp, 2H)), 1.94-2 ,07 (t, 281), 2.43-2.53 (t, 2NI), 2.78 (t, 2- 3.6 Hz, IN), 4.49 (5, 2H), 4.56 (t, 2- 7.8 Hz, IN), 5.30 (B, IN), 6.53 (444, 1-5 0.9 and 2.7 and 8.1 Hz, IN), 6.66 (lg, IN), 7.01 (944, 3-1.2 and 8.1 Hz, 1NU, 7.21 (6 32 8.1 Pv, 1H)), 7.39 (lg, IN), 7.55 ( b, ze 2.1 Cc, 1NU, 7.76 (y, 1: 3.6 Hz, 1INu; I9E NMR (282 MG, SOS): 8 - 168.10; PHU/MS: retention time: 8, 29 min.; purity: 86.7195; MS (m/z): 372.24 (MH). 7.4.286 Mm4-cyclobutyl-m2-(3,4-lichlorophenyl)-3- | Similar to the preparation of M4-(3 ,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-fluoro-2,A-pyrimidinediamine (8945394) pyrimidinediamine, M4-cyclobutyl-M2-(3,4-dichlorophenyl)-5- fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 3,4-dichloroaniline (100 mg) and 2-chloro-M4-cyclobutyl-5-fluoro-4-pyrimidinamine (50 me). IBYAME (OMO-ar): 5 1 .65-1.77 (t, 2H)), 2.07-2.20 (t, 2H), 2.24-2.33 (t, 2H), 4.42 (t, 1- 7.85 Go, 1), 7.44 (44, 4-24 and 8.7 Go, IN), 7.57 (6, 7 - 8.7 70 Hn, 18). 8.12 (4, 4-51 Hz, 18), 8.16 (y, 2: 2.7 Gu, 1H). 8.99 (Bg, 1NU, 10.49 (g, 1H); IUE

LMR (282 MGy, OM5O-yru; 8 - 162.52; RH/MIS: retention time: 13.61 min.; purity: 89.2095; MS (m/z)y: 327.10 (MAH). 7.4 .287 M24(3-chloro-4-methoxyphenyl)-M4" Similar to the preparation of Ma4-(3,4-styrenedioxyphenyl)-5-fluoro-Mm2-(3-hydroxyphenyl)-2,4-cyclobutyl-5-fluoro-2 ,4-pyrimidinediamine | pyrimidinediamine, M2-(3-chloro-4-methoxyphenyl)-M4-cyclobutyl-5-fluoro-2,4" (K945395) pyrimidinediamine is obtained as a result of the reaction of 3-chloro-4-methoxyaniline (100 mg) and 2- chloro-N4-cyclobutyl-5-fluoro-4-pyrimidinamine (50 mg). ln'MR (oM5O-a5): 5 1.63-1.75 (t, 2NI), 2.08-2, 31 (t, 4ER), 3.83 (5, ZO), 4.40 (t, 3- 7.8 Gm, KNU, 7.15 (4.3- 9.0 g, 1H), 7.34 (4y,)- 2ata8.7Gy, 1, 7.83 (4, 3-24 Hl, IN), 8.10 (4, 3- 5.4 Gy, 1H), 9.17 (og, 1HO), 10.32 (g, IN); 195 NMR (282 MHz, PM5O-yr): 5 - 162.93; LC/MS: retention time: 9.87 min.; purity: 90.1795; MS (m/z ): 323.15 (MH). 7.4.288 Ma-cyclobutyl- M2-Y3-(M- Analogous to the preparation of MA-(3,4-ethylenedioxypheny)-5-fluoro-M2-(3-hydroxyphenyl)-2,4 - cyclobutylamino)carbonylmethylene oxypyrimidinediamine, M4-cyclobutyl-M2-(34(M phenyl|-5-fluoro-2,4-pyrimidinediamine cyclobutylamino)carbonylmethyleneoxyphenylI-5-fluoro-2,4-pyrimidinediamine is obtained in (8945396) as a result of the reaction to form 3-( M-cyclobutylaminocarbonylmethyleneoxy aniline (100 mg) and 2-chloro-M4-cyclobutyl-5-fluoro-4-pyrimidinamine (50 mg). In yaYaMe (SOoStsu; 5 1.56-1.88 (t, 6H), 1.96-2.09 (t, 2NI), 2513-2.31 (ta, 4), 4.28 (t, 1 - 8.1 g, 1), 4.32 (5, 219), 4.40

Thu, 3-8.1 Hz, IN), 6.62 (aaa, 3-2 1.2 and 2.1 and 8.1 Hz, 1H), 7.09-7.20 (t, ЗН), 7.59 (0.3-4.8 gy, 1Nu, 192 UM (282 MGy, SOSIZ); 5 - 162.57; LC/MS: retention time: 9.39 min.; purity: 94.6505u; MS (m/z): 386.26 (MI). 00 s 7.4.289 Ma-cyclobutyl-M2-3,5-dichloro-4- Similar to the preparation of 1Ch4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- (3-hydroxyphenyl)-2,4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 4-cyclobutyl-M2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-2,4- Ge) pyrimidinediamine (2945397) pyrimidinediamine is obtained as a result of the reaction of 3,5-dichloro-4-methoxyaniline (100 mg) and 2-chloro-M4-cyclobutyp-5-fluoro-4-pyrimidinamine (50 mg). other pits" (0M50-a6): 5 1.63-1.76 (t, 2H), 2.07-2.33 (t, 4H), 3.78 (5, ZNU, 4.41 (t, 7- 7.8 Hz, 18), 7.81 (5, 2), 8.08 (4, 32 5.1

Hz, IN), 8.82 (bg, IN), 10.21 (g, 1H); I9E YAM (282 MHz, PM8O-yr): 5 - 163.16; RF/MS: retention time: 13.63 min.; purity: 92.8895; MS (m/zu: 357.10 (MN). (Che)

Zo 7.4290 M243,4-dichlorophenyl)-5-fluoro-MA-(2H-3- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-thiproxyphenyl)-2.4-oxo-4H -5-pyride 1,4 |oxazin-b-yl)-2,4-pyrimidinediamine, M2-(3,4-dichlorophenyl)-5-fluoro-M4-(2H-3-oxo-4H-5-pyridi 1 ,4 |oxazine-b-(e») pyrimidinediamine (2945398) yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3,4-dichloroaniline (100 mg) and 2-chloro-5-fluoro-M4-02H-3 -oxo-4H-5-pyridi-1,4|oxazin-b-yl)-4-pyrimidivamine (50 me). etc

NMR (0M8O0-46): 5 4.63 (8, 2), 7.39-7.42 (t, 31), 7.52 (44, 1 2.4 and 8.7 Gy, 1H), 8.06 (y, z-2, gi 1), 8.18 (0.3 3.6 Gu, IN), 9.46 (8, 18), 9.59 (v, 18), 1.17 (5, 18); 19E NMR (282 Ha

MgGa, 0M50-yb): 6 - 162.48; PH/MS: duration of retention: 13.30 min.; purity: 90.2495;

MC (m/z): 421.07 (MN). c 7.4.291 M2-(3-chloro-4-methoxyphenyl)-5-fluoro-YM4- | Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-(2H-3-oxo-4H-5-pyrido|1,4|oxazine-b-pyrimidinediamine . yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-chloro-4-methoxyaniline (100 mg) and 2-chloro-5-fluoro-M4-(2H-3-oxo-4H-5-pyridi E,4| )oxazin-b-yl)-4-pyrimidinamine (50 me). 18 YAM (rM5O-av): 5 3.76 (5, ZNU), 5.62 (5, 2H), 7.00 (4, 1290 Hz, « 18, 7.40 (4.35 8.7 Hz , 1), 7.47 (ti, 28), 7.50 (40.15 2.4 Hz, 173, 8.129, 22 3.3 Gy, 1H), 9.22 (5, 1H), 9.27 (8, IN), 11.15 (in, 1); 19E NMR (282 MHz, ЮМ5О-dr): 8 - 163.98; LC/MS: ssh s retention time: 10.38 min.; purity: 91 .6 92; MIS (m/z): 417.14 (MH). 7.4.292 M2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl )-5-fluoro-M2-(3-hydroxyphenia)-2,4-in» M442H-3-oxo-4H-5-pyridi 1,41oxazine-|pyrimidinediamine, M2-(3,5-dichloro-4- Methoxyphenyl)-5-fluoro-m442H-3-oxo-4H-5-p bhyp)-2,4-pyrimidinediamine (K945400) lyridine 1,4 |oxazin-b-yl)-2,4-pyrimidinediamine is obtained as a result of reaction 3, 5-dichloro-4-methoxyaniline (100 mg) and 2-chloro-5-fluoro-M44(2H,3-oxo-4H-5-pyridi I, Zoxazin-b-yl)-4" pyrimidineamine (50 mg). TV YAM (0М50-й6): 6 3.72 (5, ЗН), 4.55 (5, 2Н), 7.30 (4.12: 84 Hz,

IN), 7.35 (4, 1-8.4 Hz, 1H), 7.75 (5, 2H), 8.14 (4, 32 3.6 Hz, 1H), 9.48 (5, 1H ); URE NMR (282 (ee) MHz, OM50-dv): 6 - 162.65.

Ф 7.4.293 M243,5-dimethoxyphenyl)"5-fluoro-M4-(2H. Analogous to the preparation of Ma-3,4ethylenedioxyphenium)"3-fluoro-Mm2-(3-hydroxyphenyl)-2,4- (Ce) 42) ko 60 b5

3-oxo-4H-5-pyride E,oxazin-b-yl)-2,4- | pyrimidinediamine, M2-(3,5-dimethoxyphenyl)-5-fluoro-M4-(2H-3-oxo-4H-5-pyrimidinediamine (K945401) pyrid(1,4 |oxazine-b-yl)-2,4- pyrimidinediamine is obtained as a result of the reaction of 3,5-dimethoxyaniline (100 mg) and 2-chloro-3-fluoro-M442H-3-oxo-4H-5-pyridi I 4|oxazin-b-yl)-4-pyrimidinamine (50 mg ). Inyame (OM50-yr): 6 3.64 (5, NO), 4.62 (5, 2H), 6.06 (1-24 Hn, 1H), 6.924, 15 2.4 Hz, 2H) , 7.32 (0, 72 8.7 Hz, IN), 7.60 (4.272 8.7 Hz, IN), 8.13 (d, 12 3.6 Hz, 1NU, 9.18 (5, 18 ), 9.24 (5, 1), 1.11 (5, 19); 192 UM (282 MGy, pM5O-4r): 5 - 163.28;

PH/MS: retention time: 10.41 min.; purity: 97.0095; MS (m/z: 413.19 (MN. 7.5.294 5-fluoro-1Ch2-(3-fluoro-4-methoxyphenyl)-M4A- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro- 142-(3-hydroxyphenyl)-2,4- (2 H-3-oxo-4H-5-pyridi I oxazine-b-pyrimidinediamine, 3-fluoro-M2-(3-fluoro-4-methoxyphenyl)- M4- 42H-3-oxo-4H-5-yl)-2,4-pyrimidinediamine (K945402) pyridinium 4|oxazin-b-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-fluoro-4-methoxyaniline (100 mg) and 2-chloro-5-fluoro-M442H-3-oxo-4H-5-pyridi I, oxazine-b-yl)-4-70 pyrimidineamine (50 mg). EN 'YAME (OM50-y6u; 6 3.75 (5, ЗН), 4.62 (5, 2Н), 6.99 (B, 12 9.3 Hz, 1Н), 7.26 (00.32 2 ,4 and 9.0 Hz, 1H), 7.36 (0, 3-4 Hz, 1H), 7.45 (4.12 8.4 Hz, 1H)), 7.66 (94, knew 44 Hz , 1.811 (9.3-3.3 Hz, IN), 9.24 (5, INU, 9.32 (in, TN), 11.15 (5, NU; 19E

NMR (282 MG, OM50-dr): 6 - 163.08, - 134.90; LC/MS: retention time: 9.84 min.; purity: 93.6695; MS (m/z): 401.18 (MN). 7.4.295 Cis/trans-M4-14-(4-Cis/trans-44-44-(4-(tert-butoxycarbonylamipu)piclohexyloxy |-3-chlorophenyl| -3-fluoro»aminocyclohexyloxy)-3-chlorophenyl|- 5-| 4» methylamino)carbonylmethyleneoxyphenyl)-|aminocyclohexyloxy)-3-chlorophenyl|-5-fluoro-M2-|3-(M- 2,A-pyrimidindiamine (К945403) methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine. LC/MS : retention time: 7.06 min.; purity: 92.4995; MS (m/z): 513.43 (M). 7.4.296 5-fluoro-M2-(4-methoxyphenia)-M4-(2H- 3- Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-oxo-4H-5-pyridi 1,2|oxazine-b-1l)-2, 4-pyrimidinediamine, 5-fluoro-1M2-(4-methoxyphenyl)-m4-(2H-3-oxo-4H-5-pyridi 1,4|oxazine-b-pyrimidinediamine (8945404) yl)-2,4-pyrimidinediamine obtained as a result of the reaction of 4-methoxaniline (100 mg) and 2-chloro-5-fluoro-M4-(2H-3-oxo-4H-5-pyryl I,oxa zin-b-yl)-4-pyrimidinamine (50 mg). others

NMR (РМ5О0-46): δ 3.69 (5, 311), 4.63 (5, 2H), 6.79 (y, 12 9.0 Hz, 2H)), 7.35 (4, 1- 8.4 Hz, IN), 7.50a4, 1-90 Hn, 2H), 7.53 (a, 1-:9.0 Hz, 1NU, 8.07 (4, 3- 3.3 Gy, 1H) , 9.05 (5, 15), 9.18 (v, 1NuU, 1.13 (5, 1H); 192 МАМ (282 MHz, IM8О-46); 6 - 175.00; RHLIS: duration of retention: 8 .85 min.; purity: 10095; MS (m/z); 383.25 (Mn. 74297 142-(3,4-ethylenedioxyphenyl)-5-fluoro-ych4» Analogously to the preparation of (3,4-ethylenedioxyphenyl)-5 -fluoro-M2-(3-hydroxyphenyl)-2,4- (2H-3-oxo-4H-5-pyrido!1,4)oxazin-6-pyrimidinediamine, M2-(3,4-styrenedioxyphenyl)-5- fluoro-M4-(2H-3-oxo-4H-Z» sem 29 yl)-2,4-pyrimidinediamine (KU45405) pyridi 1,4 |oxazin-b-yl)-2,4-pyrimidinediamine is obtained as a result of reaction 3 ,4-He) ethylenedioxyaniline (100 mt) and 2-chloro-5-fluoro-M4-(2H-3-oxo-4H.-5-pyridi1,4|oxazin-6-yl)-4-pyrimidinamine (50 mes). IN NMR (pM5O-avu: 64.16 (a, 32 21 Hu, 4H), 4.62 (5, 2H), 6.67 (8, 1: 8.7 Hn, IN), 6, 98 (40, 4-2.4 and 9.0 Pi, IN), 7.27 (9, 12 2.5 Hz, 1), 7.34 (4.322 8.4

Hz, 1), 7.53 (y, 19.0 Gu, IN, 8.07 (4, 12 3.6 Hz, 1H), 9.05 (5, IN), 9.21 (v, INU, 11, 11 (in,

IN"; 195 NMR (282 MGa, OM50-46): 5 - 174.73; LC/MS: retention time: 8.94 min.; (Te purity: 97.69; MS (m/z); 411.26 (MH x 7.4.298 5-fluoro-M4-(2H-3-oxo-4H-5-) Analogous to the preparation of M4-(3,4- stylenedioxyphenyl)-5-fluoro-m2-(3-hydroxyphenyl)-2,4- (e") pyridi I, |oxazin-b-yl)-M2-(4-pyrimidinediamine, 5-fluoro-M4-21H-3 -oxo-4H-5-pyridi 1,4|oxazin-6-yl)-M2-(4-trifluoromethoxyphenyl)-2,4-trifluoromethoxyphenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 4-pyrimidinediamine (KO45406) with trifluoromethoxyaniline (100 mg) and 2-chloro-5-fluoro-M4(2H.3-oxo-4H-5-pyridin, 4-oxazine or 6-yl)-4-pyrimidinamine (50 mg). IN NMR ( OM50-yv): 6 4.64 (5, 2H), 7.18 (0, 3- 8.1 Hz, 2H), 7.38 (8, 4- 5.7 Gy, EN), 7.47 (0.32 8.7 Gy, 18), 7.73 (9, 1- 9.0 Hz, 21), 8.14 (4, 1-5 3.3 Go, IN), se 9.38 ( c, IN), 9.45 (5, 1H), 1.18 (5, 1NU; I9E YAM (282 MG, OM5O-y6): 6 - 173.29, - 68.81;

PH/MS: retention time: 12.95 min.; purity: 10095; MS (m/zu: 437.25 (MH). (se) 7.4.299 M2-(4-ethoxyphenyl)-5-fluoro-M4-(2H-3-) Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)- 5-fluoro-M2-(3-hydroxyphenyl)-2,4-oxo-4H-5-pyridinium, Coxazin-b-yl)-2,4-pyrimidinediamine, M2-(4-ethoxyphenyl)-5-fluoro- M4-(2H-3-oxo-4H-5-pyridi 1,Doxazin-6b-pyrimidinediamine (KU45407) yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 4-ethoxyaniline (100 mg) and 2-chloro»5- fluoro-M8-(2H-3-oxo-4H-5-pyridi 1,oxazin-b-yl)-4-pyrimidinamine (50 mg). 1TH nNMR (0OM50-yr6u: 5 1.30 (6.32 6, 9 Hz, ZN), 3.94 (4, 1- 6.9 Hz, 2H)), 4.63 (5, 2H), 6.77 (4.1- 8.7 Hz, « 2H)U, 7.36 (0.1-8.4 Gy, 1), 7.48 (9, 1-90 Gy, 2H)), 7.54 (d, 128.7 Gy, 1H), 8.06 (4 , 22: 3.6 Hz,

IN), 9.04 (5, TN), 9.17 (5, 18), 11.14 (5, 1NU; I9E NMR (282 MG, OM5O-4r): 5 - 175.00; - with RHU/ MS: retention time: 9.87 min.; purity: 90.82; MS (m/z): 397.28 (MH. 7.4.300 M2-(a-bugoxyphenyl)-5-fluoro-M4-(2H- 3- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-oxo-4H-5-pyridyl-4-oxazin-6-1l)-2 ,4- pyrimidinediamine, M2-(4-butoxyphenyl)-5-fluoro-M442H-3-oxo-4H-5-pyridi 1, Yaoxazin-b- and pyrimidinediamine (K945408) yl)-2,4-pyrimidinlyami: obtained in as a result of the reaction of 4-butoxyniline (100 mg) and 2-chloro-5-fluoro-M4-(2H-3-oxo-4H-5-pyridin, oxazin-b-yl)-4-pyrimidinamine (50 mg). In

NMR (OM5O-yv): 5 0.93 (t, 1- 7.5 Gy, ZN), 1.42 (peri, 1: 7.5 y, 28), 1.66 (p, 1- 6, 9 Gy, 2H), 3.89 (1.12 6.3 Hz, 2H), 4.62 (5, 2NI), 6.78 (4, 32: 8.7 Hz, 2H), 7.35 ( 4.1 8.4 Hz, IN), 7.48 (0.1 bo 9.3 Hn, NO), 7.54 (4, 1: 8.7 Hz, 1NO, 8.06 (4, 3- : 3.6 Hz, 1H), 9.04 (5, 1H), 9.17 (5, 1NU, 11.14 (5, 198; 19 UM (282 MHz, OM5O-iv): 6 - 175.02 ; LC/MS: retention time: 12.12 min.; -y 42) 60 b5 nshsh purity: 95.3695; MS (m/zu: 425.31 (MI). 74301 5-fluoro-M2-(4- phenoxyphenyl)-M4-(2H-3- Analogously to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-tihydroxyphenyl)-2,4- oxo-4H-5-pyride ( 1,4 | oxazine-b-yl)-2,4-pyrimidinediamine, 5-fluoro-M2-(4-phenoxyphenyl)-M4422H-3-oxo-4H-5-pyridi I, oxazine-b-pyrimidinediamine (K945409)yl)-2 ,A-pyrimidinediamine is obtained as a result of the reaction of 4-phenoxyaniline (100 mg) and 2-chloro-5-fluoro-M4-(2IN-3-oxo-4H-5-pyrid| 1,4 oxazin-6b-yl)-4 -pyrimidinamine (50 mg).

NMR (RMO-4b): 6 4.60 (5, 2H)), 6.91 (i, 1-:9.0 Hz, 4H), 7.05 (i, 1: 7.2 Hz, 1NU , 7.32 (t, ZN), 7.52 (8.1-8.4 Hz, IN), 7.63 (d, 15 9.0 Gy, 2H), 8.10 (0.32 3, 6 Hz, 1H)), 9.27 (5, 2), 11.14 (5,

INH 192 NMR 4282 MHz, OM50-d6): 85 - 174.19; PH/MS: retention time: 12.69 min.; purity: 10029; MS (m/z): 445.27 (МН. 7.4.302 ШМ2-(4 benzyloxyphenia)-5-fluoro-MA-(2H- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-42 -(3-Hydroxyphenyl)-2,4-3Z-oxo-4H-5-pyridi and Y-oxazin-6-yl)-2,4-pyrimidinediamine, M2-(4-benzyloxyphenyl)-5-fluoro-M4-( 2H-3-oxo-4H-5-pyrides I A |oxazine-70 pyrimidinediamine (K945410) b-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 4-benzyloxyaniline (100 mg) and 2-chloro-5-fluoro -Ma-(2H-3-oxo-4H-5-pyridi 1,4 oxazin-b-yl)-4-pyrimidinamine (50 micrograms). /H

NMR (PM50-yv): 5 4.62 (in, 211), 5.03 (5, 2H), 6.86 (4, 1-: 9.0 Ha, 2H)U, 7.31-7, 51 (t, 9H), 8.06 (a 1-33 Hz, IN), 9.05 (5, 15), 9.5 (5, 1), 11.13 (5.18); 192 NM (282 MHz, ОМ5О0-45): 6 - 170.56; LC/MS: retention time: 12.02 min.; MS (m/z): 459.33 (MN). 7.4.303 Cis/trans-Ma-|3-chloro-4-(4-(M- Carry out deprotection ups/trans-4-14-(tert-butoxycarbonylamino)cyclohexyloxy |-3-ethylamino)cyclohexyloxy|phenyl |-5 - chloronitrobenzene (5 g) using TPA, (trifluoroacetic acid, 10 ml) and fluoro-M2-(3-(M-dichloromethane) (10 ml) to form cis/lprans-4-|(4-(amino)cyclohexyloxy| -3-methylamino)carbonylmethyleneoxyphenyl)-|chloronitrobenzene. Covered with acetyl chloride in dichloromethane and triethylamine for 2,4-pyrimidinediamine (K945411) formation of cis/trans-4-14-(acetylamino)cyclohexyloxy)-3-chloronitrobenzene, which is then heated with reflux a refrigerator with a borohydride-methyl sulfide complex

THF for 1 hour to form cis/trans-3-chloro-4-14-(0M-ethylamino)cyclohexyloxy|nitrobenzene. It is restored under the conditions of hydrogenolysis using 10925 P4-C in methanol under a pressure of 4 atm for 1 hour. The catalyst is filtered off, the filtrate is evaporated to form uis/trans-3-chloro-4-14-(M-ethylamino)cyclohexyloxy aniline.

Analogous to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, cis/trans-2-chloro-M4-13-chloro-4-(4-(M-ethylamino)cyclohexyloxy | phenyl|-5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 7,4-dichloro-5-fluoropyrimidine and uis/trans"

C-chloro-4-(4-(M-ethylamino)cyclohexyloxy aniline.

Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, uis/trans-ych4-|3-chloro-4-(44-M-ethylaminocyclohexyloxyphenyl| -5- fluoro-M2-(3-(M-methylamino)carbonylmethyleneoxyphenyl)|-2,4-pyrimidinediamine is obtained in 7 as a result of the reaction of 3-(methylaminocarbonylmethyleneoxy aniline and cisltrans-2-chloro-niMa-|3- chloro -4-14-(M-ethylamino)cyclohexyloxy |phenyl|-5-fluoro-4-pyrimidinamine. LC/MS: retention time: 7.65 min.; purity: 78.8895; MS (m/z): 544 (МН. 7.4.304 5-fluoro-M2-(4-morpholinophenyl), M442Н- | Similar to the preparation of M4-4(3,4-ethylenedioxyphenyl)-5-fluoro- M2-(3-hydroxyphenyl)-2,4-

Z-oxo-4H-5"pyrido 1,4oxazin-b-yl)-2,4- | of pyrimidinediamine, 5-fluoro-M2-(4-morpholinophenyl)-M4-4(2H-3-oxo-4H-5-pyrido 1,4|oxazine-pyrimidinediamine (K945412) 6-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 4-morpholinoaniline (100 mg) and (se) 2-chloro-5-fluoro-M442H-3-oxo-4H-5-pyridci 1,4 |oxazin-b-1l)-4-pyrimidinamine (50 mg ). In

NMR (РМ5О-9в): 5 3.00 (5, 1-48 Gy, ЗН), 3.71 (5, 4- 4.8 Gy, 4Н), 4.62 (5, 2Н), 6.81 (d4.3-9.0 Ge")

Hz, 2H), 7.35 (d, 2-8.4 Gu, KN), 7.46 (9, 3-9.3 Hn, 2H), 7.56 (y, 1 8.4 Hz, IN ), 8.05 (y, 1-3.6

Hz, 1), 9.00 (5, IN), 9.13 (v, 18), 11.13 (5, INU, 19E NMR (282 MGy, РМ5О-йр5у: 6 - 175.15; or

LC/MS: retention time: 8.08 min.; purity: 97.97; MS (m/z): 438.32 (MN). 7.4.305 5-fluoro-M2-(4-isopropoxyphenyl)-M4- Similar to the preparation of IM4-(3,4-ethylenedioxyphenia)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-s (2H-3 -oxo-4H-5-pyridi 1,4|oxazine-6-pyrimidinediamine, 5-fluoro-M2-(4-isopropoxyphenyl)-M4-(213-3-oxo-4H.5-

ZB yl)-2,4-pyrimidinediamine (K945413) pyrid| i,4oxazin-b-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 4-(ee) isopropoxyaniline (100 mt) and 2-chloro-5-fluoro-M4A-(2H-3-oxo-4H-5- Pyryl and 4oxazin-b-yl)-4-ytrimidinamine (50 mg). ТН ЯМ (рМ50-дрв): 6 1.22 (0, 1- 6.3 Gy, 6Н), 4.48 (р, 1- 6.0

Hn, IN), 4.62 («, 2H)), 6.76 (y, 12 9.0 Go, 2H), 7.34 (y, 4-8.7 Hz, IN), 7.47 ( d, 72 9.0 Hz, 28), 7.53 (a, - 8.4 Hz, 1H), 8.06 (4, 22: 3.6 Gy, 1H), 9.02 (5, IN) , 9.15 (in, 1), 11.12 (5, Well; 1UE

NMR (282 MHz, OM50-46): 5 - 175.03; RC/LMS: duration of retention: 10.52 min.; purity: « 10095; MS (m/z): 411.32 (MN). 7.423406 Salt of p-toluenesulfonic acid M4-(2,2-M4402,2-difluoro-2H-3-oxo-4H-benzi I 4|oxazin-6-yl)-5-fluoro-M2-(34(7M- - s difluoro-2H-3-oxo-4H-benz||,4|oxazine-|methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (118 mg, 0.25 mmol) 6-yl)-3-fluoro-M2-| 3-0M- is suspended in apetonitrile (4 ml) and methanol (4 ml). At a temperature of 0 °C, add an aqueous solution (4 ml) of p-toluenesulfonic acid monohydrate (47.5 ml, 0.25 mmol). for 5 minutes and dried by sublimation to dryness. -6-1l)-5-fluoro-M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl)-2,-pyrimidinediamine in the form of a white solid (se) substance. 1H NMR (0M50-yru: 5 2.28 (5, ЗН ), 2.63 (df, 12 4.8 Hz, ZN), 4.33 (5, 2H), 6.58 (p,

Te 30 ha, 1, 7.09 (4, 1- 8.4 Gu, 2NU, 7.14 (4.3- 8.1 Hz, 2), 7.22 (5, IN), 7.268, 1- 8.7 Hn, ko IN" 7.36 (a, 72 2.7 Ha, 18, 7.46554.5- 7.8 Hz, 28), 7.53 (db, 15 2.4 and 8.7 Hz, 18), 7.95 (y, 72

Y 4.8 Hz, 18), 8.194.1- 4.5 Gu, 1H), 9.60 (5, 1H), 10.11 (5, 1H), 11.98 (5, 1H); 192 NMR (282 -th 42) 60 b5

MG, OM5O-yr): 6 - 162.01, - 76.80; PH/MS: retention time: 9.80 min.; purity: 190092; MS (m/z): 475.32 (MN). 7.4.307 Salt of benzoyasulfonic acid M4 - Analogously to the preparation of p-toluenesulfonic acid salt -6-yl)-5-fluoro- M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl)-2,4- benzyl|!.oxazin-6-yl)-5-fluoro-M2-13-(M- | pyrimidinediamine , benzenesulfonic acid salt M4-(2,2-difluoro-2H-3-oxo-4H-methylamino)carbonylmethyleneoxyphenyl)- | benzyl1,oxazin-b-yl)-5-fluoro-M2-(3-(M-methylamino)carbonylmethyleneoxyphenyl)-2,4-2,4-trimidinediamine (К945415) pyrimidinediamine in the form of a white solid is obtained as a result of MA reaction. (2.2-difluoro-2H-Z"oxo-4H-benz 1,oxazineb-yl-5-fluoro-M 24134" methylaminocarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (1158 me, 0.25 mmol) and benzenesulfonic acid (60 mg ). !N YAM? (0M50-yv): 5 2.63 (0, 124.5 Hz, ZE), 4.33 (5, 20), 6.56 (4, 72 2.4 and 6.9 Gm, 1H)U, 7, 10-7.37 St, WEU), 7.52-7.59 (z, ZN), 7.96 (4, 1- 4.5 Hz, 1H), 8.18 (4, 2: 4.5 Hz, 1), 9.53 (5, EN), 10.03 (5, 180), 11.98 (in, 13); 19E NMR (282 MG,

OM5O-4: 5- 162.30, - 76.83; PH/MS: retention time: 9.79 min.; purity: 10095; MC (miv): 475.34 (MN). 7.4.308 Ш4-(2,2-dimethyl-2Н-3-oxo-4Н-5» Similar to the preparation of М4-(3,4.ethylenedioxyphenyl)-5-fluoro-М2-(3-hydroxyphenyl)-72,4- pyrido|1,4|oxazin-b-yl|-5-fluoro-M2-|4-|pyrimidineliamine, M4-4(2,2-dimethyle2H-3-oxo-4H-5-pyryl 1, Zoxazin-b- yl)-5-fluoro-M2-(4-methoxycarbonylpiperazino)phenyl|- (4-(4-methoxycarbonylpiperazino)phenyl)|-2,4-pyrimidinediamine is obtained as a result of 2,4-pyrimidinediamine (K945416) reaction 4-(4 -methoxycarbonylpiperazino)aniline (100 mg) and 2-chloro-M4-(2,2-dimethyl-2H-3-75 oxo-4H-5-pyridi 1,oxazin-6b-yl)-5-fluoro-4-pyrimidinamine (50 mg). IN YAM (rmM5o-av): 51.43 (z, 6H), 2.99 (i, 12: 5.4 Gy, 4H), 3.49 (5.72 5.1 Gy, ANU, 3.61 (5, ZN), 6.82 (d, 45950 Hz, 2), 7.37 (90.7: 8.4 gy, IN), 7.47 (4, 12" 9.0 Gu, NU, 7.55 (4, 12: 8.1 Gy, 18), 8.06 (4, 3-- 3.6 Hz,

IN), 9.02 (5, IN), 9.14 (in, TN), 11.08 (5, IN); I9E NMR (282 MGy, OM5O-46): 6 - 164.38;

LC/MS: retention time: 10.24 min.; purity: 10990; MS (m/zu: 523.45 (MH). 7.4.309 M2-I14-(M-acetyl-M-methylamino)phenyl|»- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5"fluoro-142 -(3-tihydroxyphenyl)-2,4-

M4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrimidinediamine, 1Ch2-14-(M-acetyl-M-methylamino)phenyl|-M4-(2,2-dimethyl-2H-3- oxo-4H-pyride|1,4oxazin-6b-yl)-5-fluoro-2,4-5-pyryl 1,4)oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result reactions of 4-pyrimidinediamine (K945417) (M-acetyl-M-methylamino)aniline (100 mg) and 2-chloro-M4-(2,2-dimethyl-2H-3-oxo-4H-5-pyryl 1,oxazine- β-yl)-5-fluoro-4-pyrimilinamine (50 mg). IN NMR (OM50-yf): 8 1.43 (5, bH), 1573 (5, ZNU, 3.08 (5, ZNU, 7.11 (4, 3- 8.7 Hn, 2NU, 7, 41 (y, 1-8.4 Gy, 1H), 7.49 (0.2-8.7

Ha, 1 Nu, 7.68 (a, 7-8.7 Hz, 2H), 8.13 (4, 3-36 Hz, 1 NU, 9.35 (5, 1H), 9.40 (5, EN), 11.12 (5, 10; 19E NAM (282 MGy, rM8o-y6y: 6 - 162.87; RU/MS: retention time: 10.03 min.; purity: 10055; MS (m/z) ; 452.26 (МН"). sem : - - - - 7 7.4.310 142-144(M-acetyl-M-stylamino)phenyl|- Similar to the preparation of 4-(4-methoxycarbonylpiperazino)nitrobenzene, M-acetyl-Mm - Gee)

Ma-(2,2-dimethyl-2H-3-oxo-4H-5-ethyl-4-nitroaniline is obtained as a result of the reaction of M-ethyl-4-nitroaniline (1 g) and pyrido( and oxazin-b-yl)- 5-fluoro-2,4- acetyl chloride (1 mg). TN NMR (SOSIS); 5 1.15 (i, 2-7.2 Hz, ZNU, 1.94 (8, ZNU, 3.81 (a, 32 pyrimidinediamine (K945418) Ш 7.2 Hz, 2NU, 7.36 (y, 3: 9.0 Hz, 2Н), 8.30 (0, 3- 8.7 Hn, 2Н).

M-acetyl-M-ethyl.-4-nitroaniline is reduced under conditions of hydrogenolysis using 10995

Ra-C in methanol ice with a pressure of 2.7 atm during | hours The catalyst is filtered. (Se)

The filtrate is evaporated to form 4-(14-apethyl-M-ethylamino)aniline. TN yaYAMe (SOSIZ): 6 1.09 (6, 32 7.2 Go, ZN), 1.82 (5, ZNU, 3.68 (4, 12: 7.2 Hz, 281), 6.79 ( 4, 22 8.4 Hy, b 2H), 5.95 (4, 1-81 Hn, 28).

Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, M2-(4-(M-acetyl-M-ethylamino)phenyl|-144-( 2,2-dimethyl-2H-3-oxo-4H-5-h-pyrido(1,4)oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 4414-acetyl-M- ethylamino)anilic (100 mg) and 2-chloro-M442,2-pimethyl-2H-3-oxo-4H-5sem pyridP,4)oxazin-6-yl)-5-fluoro-4-pyrimilinamine (50 mg) . 6.9 Hz, 281), 7.06 (0.1-8.7 Hz, 7H), 7.40 so (4.1-8.7 Hn, IN), 7.48 (0.1-8.1 Hz, 1NI), 7.69 (d, 2- 8.7 Gu, 2NI), 8.13 (d, 1- 3.3 Gy, IN), 9.35 (5, 1), 9.40 ( 5, IN), 11,12 (v, I NU; IUE NMR (282 MGy, OM5O-iv): 6 - 162.90; LC/MS: retention time: 10.51 min.; purity: 10095; MS ( m/z): 466.25 (MY, 74311 M2-14(4-acetylpiperazino)phenyl|-M4- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2 . 2-dimestil-2H-3-oxo-4H-5-pyrido 1,4|oxazin-b-yl)-5-fluoro-2,4-pyrido(1,4|oxazin-6-yl)-5- fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 4-(4- 406 pyrimidinediamine (5945419) acetylpiperazino)aniline (100 mg) and 2-chloro-M4-(2,2-dimethyl-2H-3-oxo-4H- 5- shsh c pyrido(1,4|oxazin-b-yl)-5-fluoro-4-pyrimidinamine (50 mg). TN NMR (0M50-46): 5 1.43 (5, 6H), 2.03 (5. ZN), 2.96 (32 5.1 Hz, 28), 3.03 (5 2- 4.8 gy, 2H), 3.56 (t, 4H), 6.82 (y, 1-5 90 and Hz, ?H), 7.37 (4.1: 8.4 y, 18), 7.47 (4, 2- 8.7 Gy, 2), 7.56 (8, 12 8.1 Hz, 15, 8.05 (d, 12 3.6 a Gy, 1), 9.02 (z, 1Н ), 9.13 (5, 18), 11.08 (5, 1H); HER NMR (282 MIch, OMBO-46): 6 - 164.40;

LC/MS: retention time: 8.70 min.; purity: 97.70; MS (m/z): 507.55 (MN). 7.4.312 M2-14-(M-acetyl-M-methylamino)phenyl- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-5-fluoro- M44(2H-3-oxo-H-5-pyrimidinediamine, M2-14-40M-acetyl-ych-methylamino)phenyl)-5-fluoro-M4-(2H-3-oxo-4H-5" (se) pyride | 1,oxazin-b-yl)-72,4-pyride 1,oxazineb-yl)-2,2-pyrimidinediamine is obtained as a result of the reaction of 44(M-acetyl-tyrimidinediamine (945420) M.methylamine)aniline (100 mg) and 2-chloro-5-fluoro-M4-(2NH3-oxo-"H"5"pyridi1,4)oxazn-b" with yl)-4-pyrimidinamine (50 mg). IN' NMR (0M50-yv): 6 1.74 (5, ЗН), 3.09 (5, ЗН), 42.64 (5, 2Н), шу 7.13 (9, 32: 8.7 Go, 2Н), 7.40 (4, 32-8.7 Hz, 19), 7.50 (4, 7-8.7 Hn, 10), 7.69 (y, 7-2 8.7 Hz, 2H), - and (Se) 42) ko 60 b5

8.13 (4, 12 3.3 Gy, IN), 9.34 (5, 1H), 9.39 (5, IN), 11.16 (5, IN); 19E NMR (282 MHz, OMI5O-dru 0 - 171.37; LC/MS: retention time: 9.14 min.; purity: 91.4395; MS (m/z): 424.50 (Mn. 7.4.313 142-144(M-acetyl-M-ethylamino)phenyl|-5- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-fluoro-M4- (2H-3-oxo-4H-5-pyrimidinediamine, M2-(4-(M-acetyl-M-ethylamino)phenyl-5-fluoro-M4-(2H-3-oxo-4H-5- pyridi I,2 )oxazine-6-1l)-2,42 pyrid|1,4oxazine-b-yl)-2,4-pyrimidindiamine is obtained as a result of the reaction of 4-(0M-acetinl-pyrimidinediamine (K945421) Mi-ethylamino)aniline (100 mg ) and 2-chloro-5-fluoro-M4-(2H-3-oxo-4H-5-pyridine I,4|oxazin-b-yl)-4-pyrimidinamine (50 mg). 1N NMR (0M5O-4u) : 8 0.98 (i, 1-2 6.9 Gy, ZNU, 1.69 (in, ZN), 3.57 (d, 1-2 6.9 Hz, 2H), 4.63 (85, 2H), 7.08 (d,3--8.7 Hz, 2H), 7.39 (y, 32 8.4 Hz, 180), 7.50 (y, 1-84 gy, 1), 7 .69 (4, 3- 9.0 Hz, 2H), 8.13 (y, 7: 3.6 Gu, 1H), 9.34 (z, 1H), 9540 (5.19), 116 (5 . 7 (MN. 7.4.314 M2-(3,4-dimethoxyphenyl)-5-fluoro-M4A-4(2H- | Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fcor-M2-(3-hydroxyphenyl)-2, 4"

Z-oxo-4H-5-pyridi!,4oxazin-b-yl)-2,4- | pyrimidinediamine, M2-(3,4-dimethoxyphenia)-5-fluoro-M4-(2H-3-okoso-4H-5-pyrimidinediamine (2945422) pyrid I, 4|oxazin-6-yl)-2,4-pyrimidinediamine obtained as a result of the reaction of 3,4-dimethoxyaniline (100 mg) and 2-chloro-5-fluoro-M4-(3H-3-oxo-4H-5-pyridi 1,4|oxazinob-yl)-4-pyrimidinamine (50 mg ). !H NMR (OMBO-4): 5 3.64 (v, ZN), 3.68 (5, ZNU, 4.63 (5, 7), 6.79 (401-900 Hz, 1), 7, 20-7.23 (ti, 2NO), 7.33 (4, 3- 8.7 Hz, 1NO, 7.59 (y, 72 8.7 Hz, 1H), 8.08 (4, 1-3 ... MS: retention time: 8.35 min., purity: 94.2195, MS (m/z): 413.30 (MH), 7.A.315 Ma-(2,2-dimethyl-2H-3-oxo -4H-5- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-pyridi I,4)oxazin-b-yl)-5-fluoro-M2 -(4-pyrimidinediamine, M4-(2,2-dimethyl-2H-3-oxo-4H-5-pyride and, Poxazin-b-1l)-5-fluoro-M2-(4-morpholinophenyl)-2,4 -pyrimidinediamine morpholinophenyl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 4-morpholinoaniline (K945423) 41100 mg) and 2-ylur-M442,2-dimethyl-2H-Zoxo-4H-5-pyrid/!,Poxazin-b- yl)-5-fluoro-4-pyrimidinamine (50 mg). 1N NMR (OM5O-y6): 6 1.43 (5, 6H), 2.99 (b, 12: 4.8 Hz, 4H), 3 .72 (i, 1- 4.8 Gy, 4), 6.80 (y, 1-- 8.7 Hz, 2H), 7.36 (4, 22 8.4 Gy, 1NU, 7.46 ( 4, 1-9.0 Go, 2NU, 7.55 (0, 128.7 Hz, IN), 8.06 (4, 12 3.6 Hz, 1H)), 9.00 (5, 1H), 9.13 (5, 1H), 11.09 (in, 1H); 192 YAM" (282

MGy, RM50-4r6): 5 - 173.16; РЧ/МС: duration of retention; 9.59 min.; purity: 10095; MS (m/z; 466.28 (MH. 7.4.316 M2-(340M- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-feoro-M24(3-hydroxyphenyl)-2,4- piclobutylamino)carbonylmethyleneoxy pyrimidinediamine, M2-13-(M-nicklobutylamino)carbonylmethyleneoxyphenyl|)-M44(2,2-Ha phengel)-M4-(2,2-dimethyl-2H-3-oxo-4H.5. | dimethyl-2H-3 -oxo-4H-5-pyridi 1.4|oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine is obtained in pyride 1,4|oxazni-b-iya)-5-fluoro-2,4- as a result reaction of 3-(cyclobutylaminocarbonipmethyleneoxy)aniline 1100, mg) and 2-chloro-M4-(o)pyrimidinediamine (K945424) (2,2-dimethia-2H-3-oxo-4H-5-pyridi 1,4|oxazine-b -yl)-5-fluoro-4-pyrimidinamine (50 mg). 1H NMR (0M50-46): 5 1.42 (5, 6H), 1.57-1.66 (t, 2NU, 1.90-2.04 (t, 2H)U, 2.12 (t, 2), 4.25 (a,3-8.4 Hz, IN), 4.33 (5, 2H)), 6.46 (4th, 12 1.8 and 8.1 Gm, 18), 7.08 ( 4-8, Hz, NO), 7.25 (9, 1-84 Gy, 1), 7.35 (t, 1), 7.36 (d, 7- 9.0 Gy, IN), 7, 63 (0.35 9.0 Hn, IN), 8.12 (6.75 3.6

Hn, 1H), 8.23 (8, 12 7.5 iv, 1), 9.22 (in, 1H), 9.26 (5, 1H), 11.06 (5, IN); EE NMR (282 MIG, (Ce)

OM5O-afi: 6-1741; РХ/MIS: length of stay; 11.46 min.; purity: 97.6595; MS (m/zu: 508.45 (MH). b» 7.4.317 5-fluoro-M2-144(4- Carry out the reaction between 1-(4-nitrophenyl)piperazine (and g), odmethane (0.3 ml ) and methylpiperazino)phenyl-M4-(2H-3-oxo-| with sodium hydride (500 mg) in THF (10 ml) overnight at room temperature. or 4nH-5-pyridi I, Jaoxazin-6b-11)-2 ,4- The resulting solution is diluted with water. The yellow precipitate is collected by filtration, washed with pyrimidinedimine (5945426) with water to form 4-(4-methylpiperazino)nitrobenzene as a yellow solid. /H NMR (SOSIS): 6 2.45 (in, ZI), 2.69 (5.32: 5.1 Hz, 4H)), 3.52 (i, 7-- 5.1 Hz, 4H), 6.83 (4.532 9.3 Hz, 2H), 8.12 4.3-9.3 Hz, 2H), with 4-(4-Methylperazino)nitrobenzene is reduced under the conditions of hydrogenolysis using 1095 Va-C in methanol under a pressure of 2.7 atm during I! hours The catalyst is filtered. The filtrate is evaporated to form 4-(4-methylpiperazino)aniline.

IN NMR (SOSIZ); 6 2.47 (5, ZN), 2.75 (, 12 5.1 Gu, 4H), 3.16 (25 5.1 Hn, AN), 6.65 (y, 129.9

Hz, 2), 6.81 (90.1 8.7 Hn, 2H). "

Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)5-fluoro-M243-hydroxyphenyl)-2,4-pyrimidinediamine, 5-fluoro-M2-(4-(4-methylpiperazino)phenyl|-M4-(2H-Z- oxo-4H-5-pyridi 1,4oxazin-6-1l)-2,4-pyrimidinediamic is restrained as a result of the reaction of 4-(4- shshc methylpiperazino)aniline (100 mg) and 2-chloro-5-fluoro-M4- (2H-3-oxo-4H-5-pyrid|1,Poxazin-6-yl)-4-pyrimidinamine (50 mg). IN NMR (0M50-yb): 6 2.85 (5, ЗН), h 3 .16 (t, 2H), 3.48 (t, "H), 3.59 (t, 2H)), 4.63 (5, 28), 6.87 (y, 1- 9.0 Hz, ?H), 7.36 (4.12 8.7 and » Hz, 1), 7.50 (4.27: 9.0 Gu, 2H)U, 7.544, 328.1 Hz, 18), 8.074, 1-36 Hz , 1H), 9.08 65. 15), 9.21 (5, EN), 116 (in, 18); I9E NMR (282 MGy, OM5O-4r): 8 - 172.68; LC/MS: retention time: 5.67 min.; purity: 10095; MS (m/z): 451 (MN). 7.4.318 M44(2,2-dimethyl-2H-3-oxo-4-52 Analogously to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- (ee ) pyrid(and 4|oxazin-6-yl)-5-fluoro-M2-|4-(4- |pyrimidinediamine, M4-(2,2-dimethyl-2H-3-oxo-4H-5-pyrid| ! oxazin-6-yl)-5-fluoro-M2-14-methylpiperazino)phenia-2,4-(4-methylpiperazino)phenyl|-2,4-pyrimidinediamine is obtained as a result of the reaction of 4-(4- with pyrimidinediamine (5945427) methylpiperazino)aniline (100 mg) and 2-chloro-Ma-(2,2-dimethyl-2H-3-oxo-YAN-5- pyridyl, oxazin-b-yl)-5-fluoro-4-pyrimidinamine (50 mg). 1 NMR (pM5O-afu.; 5 1.43 (5, -y (Ce) 42) ko 60 b5

6H), 2.71 (5, ZNU, 3.16 (it, ZN), 6.84 (y, 7-9.0 Hz, 28), 7.37 (0, 2-84 Hz, 1), 7.49 (4.199

Hz, 2), 7.54 (d0, 2: 8.4 Hz, IN), 8.07 (а, 12 3.6 Hz, 1Н), 9.05 (5, 1Н), 9.18 (5 . z): 479.25 (МН). 74319 М2-(3,5-dimethylphenyl)-5-fluoro-М4-2Н- Similar to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-ЎМ2-(3- hydroxyphenyl)-2,4-3-oxo-4H-5-pyridi 1,4|oxazin-6-yl)-2,4-|pyrimidinediamine, M2-(3,5-dimethylphenia)-5-fluoro-Ma- (2H-3-oxo-4H-5-pyride 1,4|oxazine-pyrimidinediamine (2945432) 6-yl)y-2,4-pyrimidinediamine is obtained as a result of the reaction of 3,5-dimethylaniline (100 mu) and 2-chloro -5-fluoro-M4-(2H-3-oxo-4H-5-pyridyl,Doxazin-6-yl)-4-pyrimidinamine (50 mg). 1H

NMR (OM50-4yv): 5 2.17 (5, 6), 4.62 (5, 2H), 6.52 (5, IN), 7.22 (5, 2H), 7.34 (4.72 8 ,4 Hz, 155, 7.57 (4.12 8.4 Hz, KN), 8.11 (4, 3- 3.6 Co, 18), 9.10 (5, 1H), 9.19 ( 5, 1H), 11.14 (5.18); 192 UM? (282 MHz, OM5O-46); 6 - 172.16; LC/MS: retention time; 11.34 min.; 70 purity: 90, 0495; MS (m/z): 381.23 (MH). 7.4.320 M2-(3,5-dimethylphenyl)-M4-(2,2-dimethyl- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl) -5-fluoro-I42-(3-hydroxyphenyl)-2,4-?H-3Z-oxo-4H-5-pyrido|1,oxazin-b-yl)-|pyrimidinediamine, M2-(3,5- dimethylphenyl)-M4-2,2-dimethyl-2H-3-oxo-4H-5-5-fluoro-2,4-pyrimidinediamine (K9454353) pyrid (1,4oxazine-b-1l)-5-fluoro-2, 4-pyrimidinediamine is obtained as a result of the reaction of 3,5-dimethylaniline (100 mg) and 2-chloro-M4-(2,2-dimethyl-?2H-3-oxo-4H-5-pyrid| 1, Choxazin-bil-yl )-5-fluoro-4-pyrimidinamine (50 me). IN NMR (OMBO-yr): δ 1.42 (5, 6H), 2.16 (5, 6H), 6.51 (5, ZNU, 7.23 (5, 7NU, 7.35 (0, 1- 8.4 Hz, 1), 7.599, 1 8.1 Hz, 1H), 8.11 (4, 2: 3.6 Gu, 18), 9, 10 (5, ENU. 9.18 (5, 10), 11.08 (5, IN); 192 YAM (282 MGy, РМ5О-й6): 8- 172.19; VH/MS: retention time: 13.05 min.; purity: 95.7195; MS (m/z): 409.30 (MH. 7.4321 5-fluoro-M2-(3-isopropylphenyl)-M4-(2H-3- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro- M2-(3-hydroxyphenyl)-2,4-oxo-4H-5-pyrido|I,4oxazin-b-yl)-2,4-pyrimidinediamine.5-Fluoro-IM2-(3-isopropylphenyl)-M4-( 2H-3-oxo-4H-5-niride|1,4)oxazine-pyrimidinediamine (K945434) 6-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-isopropylaniline (100 me) and 2-chloro-5- fluoro-M4-(2H-3-oxo-4H-5-pyrido|/1,4|)oxazin-6-yl)-4-pyrimidinamine (50 mg), other

NMR (OM5O-yru 5 1.15 (4, 1- 6.9 Hz, 6H), 2.74 (p, 1- 6.9 Hz, 18), 4.63 (5, 7NI), 6.76 (d, 1- 7.8 Ha, NN), 7-7, So, 1), 7.34 (4.12 8.7 Hn, IN), 7.42 (5, 1H), 7.51 ( 4.129 Hz, 1H),7.57 (4, 1- 8.4 Hz, IN), 8.11 (4, 2- 3.6 Hz, 18), 9.15 (5, 18), 9.21 (5, IN), 11,15 5, Well; 192 YMmR (282 MG, OM5O-ar): 5 - 172.02; PH/MS: retention time: 12.40 min. purity: 92.20; MS (m/z)y: 395.28 (MH. 7.4.322 M2-(3-chloro-4-methylphenyl)-5-fluoro-Ma4- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro -M2-(3-hydroxyphenyl)-7,4- (2H.3-oxo-4H-5-pyrido| 1 Yaoxazine-b-pyrimidinediamine, M2-(3-chloro-4-methylphenyl)-5-fluoro-M442H -3-oxo-4H-5-Hayl)-2,4-pyrimidinediamine (5945439) pyrido(1,4 |oxazin-b-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3-chloro-4- 11 )-2,4-pyrimidinidiamine (2945439) methylaniline (100 me) and 2-chloro-5-fluoro-M4-(2H-3-oxo-4H-5-pyridi| 1, oxazin-b-yl)-4- Go) pyrimidineamine (50 mg). INYAMe (0M5O-yr): 52.22 (5, ЗН), 4.63 (in, 2H), 7.13 (y, 12 8.7 Ha, 1H)U, 7.38 (iz, 2H), 7.28 (4.3 8.4 HY, 1H), 7.83 (4, 22 2.1 HY, EN), 8.13 (a, 1- 3.3 Hu, HO), 9.31 ( c, 1H), 9.33 (5, 18), 11.13 (c, 1H); I9E NMR (282 MHz, PM8O-4r): 5 - 171.47; RH/MS: retention time: 12.66 min.; purity: 94.85929; MS (m/z): 401.13 (MAN. «se 7.4.323 5-fluoro-M2-(3-methoxy-5-) Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-( 3-tihydroxyphenyl)-2,4-trifluoromethylphenyl)-M4-(2H-3Z-oxo-4H- | pyrimidinediamine, 5-fluoro-M2-(3-methoxy-5-trifluoromethylphenyl)-M4-(2H-3-oxo -4H-5- Tech!5-pyridi 1,4)oxazin-b-yl)-2,4-pyridi 1.Aoxazin-6b-yl)-2,4-pyrimylindiamine is obtained as a result of the reaction of 3-methoxy-5- pyrimidinediamine (5945440) trifluoromethylaniline (100 mg) and 2-chloro-5-fluoro-M442H-3-oxo-4H-5-pyride | 1, oxazine-b-yl)-4-pyrimidinamine (50 mg). IN NMR (0M8O-yv): 6 3.74 (5, ZN), 4.63 (v, 2H), 6.72 (5, 1), h- 7.328, 1-84 Ho, 1H), 7, 51 (a, 8.7 Hz, 1H)), 7.56 (5, 1H)), 7.64 (5, IN), 8.18 (4, 1-3.3 Gu, 1H), 9, 36 (5, 1H), 9.55 (5, 18), 11.12 (in, IN); I9E YAM (282 MGy, OM8O-yr): 6 - 170.42; with

PH/MS: retention time: 13.14 min.; purity: 86.6596; MS (m/z); 451.30 (MN). 3o 7-4.324 5-fluoro-M2-(indol-v-yl)-M4-(2H-3-oxo- Analogous to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-tihydroxyphenia) -2,4» co 4H-5-pyridi 1,4)oxazin-b-yl)-2,4-pyrimidinediamine, 5-fluoro-M2-(1ndol-b-yl)-m4-(2H-3-oxo -4H-5-pyride 1,4oxazin-6-yl)-pyrimidinediamine (K945443) 2,4-pyrimidinediamine is obtained as a result of the reaction of b-aminoindole (100 mg) and 2-chloro-5-fluoro-M4-(2H- 3-oxo-4H-5-pyrido|1,oxazinob-yl)-4-pyrimidinamine (50 mg). Yin YAM (RM5O-yb): 5 4.62 (5, 2), 6.30 (8, IN, 7.17 (t, 2NU, 7.29 (4, 72 8.7 Gu, INU, 7.35 (8,15 8.7

Hz, in), 7.7544,1-8.7 Go, IN), 7.82 (5, IN), 8.10 (4, 7- 3.6 Hz, 18), 9.08 (5, 18), 9.11 (5, IN), « 10.84 (in, CPU), 111 (5, 1); Y9E YAM (282 MHz, PM5O-46): 6 - 172.73; PH/MS: duration of retention: 8.52 min.; purity: 81.7495; MC (m/z): 392.30 (MN). - c 7.4.325 Ma-(2,2-dimethyl-2H-3-oxo-4H.Z- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2, 4- pyridi 1,4 oxazin-6-yl)-5-fluoro-M2-pyrimidinediamine, M4-(2,2-dimethyl-2H-3-oxo-4H-5-pyride 1,4 |oxazin-b-yl )-5-fluoro-M2- in! (indole-b-yl)-2,4-pyrimidinediamine (indole-b-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of b-aminoindole (100 mg) and schi (v945444) 2-chloro-M4- (2,2-limethyl-2H-3-oxo-4H-5-pyrido|1,4|oxazin-6-yl)-5-fluoro-4-pyrimidinamine (50 mg). YIN YAM? (OM5O-4r): 6 1.42 (5, 6H), 6.30 (5, 1H), 7.18 (t, 2H), 7.29 (d, 1- 8.4 Hz, 1H), 73510, 8.7 Hz, 180), 7.77 ( 4, 3- 8.7 Hz, IN), 7.80 (5, 18), 8.10 (4, 7- 3.6 Gy, IN), 9.02 (in, 1H, 9.09 (5, 1H), 10.84 (in, 180), 11.04 (x, INU; UR NMR (282 MHz, rmM50-45u 6 - 172.86; (ee) RF/MS: retention time: 9.91 min.; purity: 98.0195; MS (m/z): 420.18 (MH). 7.4. 326 M243,5-dichlorophenyl)-5z-fluoro-M442H-3- | Similar to the preparation of IM4A-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2.4-ke oxo-4H-5- pyride I. Yaoxazin-b-yl)-2,4-pyrimidinediamine, M2-403,5-dichlorophenyl)-5-fluoro-Ich4-(2H-3-oxo-4H-5-pyridi 1. Yaoxazin-b- - and (Ce) 42) ko 60 b5 pyrimidinediamine (K945454) yl)-2,a4-pyrimidinediamine is obtained as a result of the reaction of 3,5-dichloroaniline (109 mg) and 2-chloro-5-fluoro-ma-(2H-3- oxo-4H-5-pyridi I, 4oxazin-6-yl)-4-pyrimidinamine (50 mg). In

NMR (0M50-46): 5 4.62 (5, 2H)), 6.99 (I, 1: 1.8 Gy, IN), 7.38 (v, 2H), 7.70 (4,1- 2.1. Hu, 2H), 8.19a ,1- 3.6 Hu, 13, 9.52 (5, IN), 9.66 (z, 1H), 11.17 (in, 1H); 19 NMR (282 MHz, OM5O- 46: 5 - 170.19; LC/MS: retention time: 14.05 min,; purity: 85.53; MS (m/z); 42121 (MIG). 7.4.327 M2-(3-bromophenyl )-5-fluoro-1M4-22H-3- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-oxo-4H-5-pyride | I Yaoxazin -6-yl)-2,4-pyrimidinediamine, M2-(3-bromophenyl)-5-fluoro-M4-(2H-3-oxo-4H-5-pyridi1, oxazin-b-yl)-pyrimidinediamine (KU45455) 2,4-pyrimidinediamine is obtained as a result of the reaction of 3-bromoaniline (100 mg) and 2-chloro-5-fluoro-Ma«(2H-3-oxo-4H-5-pyridinium, 4|oxazin-b-yl) -4-pyrimidinamine (50 mg). NMR (0OM5O-av): 5 4.63 (5, 2H), 7.02 (44d, 1: 0.9 and 1.8 and 7.8 Hz, IN), 7.13 and, 3- 8.1 Go, 1H), 7.39 70 (4,1 - 8.7 Hz, 1H), 7.47 (4.4 8.1 Hz, 1), 7.52 (34, 1- 0.9 and 8.1 Go, IN), 7.99 (1, 12 1.8 Hz,

IN), 8.169.1- 3.6 Hz, 1H), 9.40 (5, T1H), 9.47 (5, 18), 11.17 (8, 1H); 19E NMR (282 MGu, pPM5O-46): 5 - 170.91; PH/MS: retention time: 12.31 min.; purity: 100; MS (m/z: 431.20 (MH. 7.4.328 M2-(3-tert-butylphenyl)-5-fluoro-M4-(2H- | Similar to the preparation of Ma4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2 -(3-hydroxyphenia)-2,4- 3-ocoo-4H-5-pyride | 1,4 oxazin-b-yl)-2,4- | pyrimidinediamine, M2-(3-tert-butylphenyl)-5- fluoro-ma-(2H-3-oxo-4H-5-pyrido(1,4|oxazine-pyrimidinediamine (945456) o-yl)-2,4-pyrimidindiamine is obtained as a result of the reaction of 3-tert-butylaniline (100 mg) and 715 2-chloro-5-fluoro-M442H-3-oxo-4H-5-pyride|1,4|oxazin-6-yl)-4-pyrimidinamine (50 mg).

NMR (0M50-d6): 5 1.23 (5, 9Н), 4.62 (5, 2Н), 6.91 (0.128.1 Hz, 1НУ 7 (72 8.1 Hu, 1Ну, 7.34 (0, 1- 8.4 Hu, 1Н), 7.48 ( 5, 1), 7.58 (5, 1), 7.63 (y, 3-99 Ha, IN), 8.11 (4, 1-36 Hu, 1NU, 9.12 (5, IN), 9.16 (5, EN), 11.12 (5, 1H); 19E NMR (282 MHz, PM5O-yf): 5 - 171.99;

РХ/MS: retention time: 13.16 min.; purity: 93.0395; MS (m/1): 409.29 (MH), 7.4.329 2-(3,4-difluorophenyl)-5-fluoro-M4-22H-3- | Analogously to the tattoo M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2.4-oxo-4H-5-pyride| I 4 oxazin-b-yl)-2,4-pyrimidinediamine, M2-(3,4-disorbhenia)-5-fluoro-M4-(2H-3-oxo-4H-5-pyridi 1,4|oxazine-b - pyrimidinediamine (2945458) yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 3,4-liftoraniline (100 me) and 2" chloro-5-fluoro-M4-(2H-3-oxao-4H-5-pyridi I , 4oxazin-b-yl)-4-pyrimilinamine (50 mg). In

NMR (0M5O-yv): 5 4.63 (5, 2H)), 7.27 (t, 2H), 7.38 (v, 2NI), 7.88 (449, 12 2.7 x 8.1 and 14.1

Ha, IN), 8.15 (4, 1- 3.6 Gy, 1H), 9.46 (5, 1H), 9.48 (5, 13), 11.17 (5, IN); 19E NMR (282 MHz,

ОМ5О-й6): 8 - 162.44, - 148.50, - 138.13; РХ/MS: retention time: 11.63 min.; purity: 84.8995; MC (m/z): 389.25 (MN). c 2 of o 7.4330 (52)-2-methyl-b-nitro-3-oxo-4H- To a solution of 2-amino-4-nitrophenol (6.6 g) in DMF (100 ml) at 0 "C is added immediately all benzene and Doxazine solid substance 9595 MaN (1 g). The solution is stirred at 0 "C for 20 minutes, then at room temperature for 1 hour. (5)-(-)-methyl-2-chloropropionite (5 g) is added immediately, the reaction mixture is heated with a reflux condenser at 85 °C overnight. The reaction mixture is concentrated and the residue is partitioned between BIODAs and water. The aqueous phase extracted with BIO Ac, and the combined organic layers were washed three times with water, then once with brine, dried over Me5O4, filtered, and the volume reduced on a rotary evaporator to approximately 15 mL. :4. The pure fractions are combined and evaporated; the crude product is recrystallized from OA with/hexanes to form (5)-2-methyl-b-nitro-3-oxo-4H-benz| 1, Poxazin. "H NMR (OM5O-46u : 5 7.82 s (49, 18), 7.76 (a, IN), 7.12 (y, 1), 4.90 (a, 1), 1.42 (4, ZN); LC/MS: purity: 100 5; MS (m/z: 209 (MN). se 7.4331 (5)-6-amino-2-methyl-3-oxo-4H- To a solution of (5)-2-methyl-b-nitro-3-oxo-4H- benz(I,4oxazine (2.5 g) in 250 ml of EUN/LEO Where benz|!,oxazine (1:11; by volume) add 500 mg 1095 Ra/C (Perivza), reaction this amount is hydrogenated in (ee) a Parr apparatus under a pressure of 3.4 atm for 1 hour. The resulting substance was filtered through celite, evaporated and dried in vacuo to give 2.3 g of (5)-6-amino-2-methyl-3-oxo-4H-benzi-1,4|oxazine. "H NMR (IM50-46): δ 6.60 (6, MH, 6.12 (t, 2H), 4.40 (94, 185), 1.32 (0, ZN); LC/MS: purity : 100 95; MS (m/z): 179 (MN. 7.4.332 (8)-2-methyl-b-nitro-3-oxo-4H- Analogously to the synthesis of (5)-2-methyl-b-nitro- 3-oxo-4H-benz 1,42oxazine, (K)-2-methyl-benzi 1,4oxazine b-nitro-3-oxo-4H-benz 1,4oxazine is obtained as a result of the reaction (K)- (5)-methyl-2-chloropropionate with 2-amino-4-nitrophenol. "H NMR (PM5O0-46): 5 7.82 (49, 1H), 7.76 (a, - 18), 7.12 (9, IN, 4.90 (9, 18), 1.42 (d, ZNU; RH/MS: purity: 190 95; MS (m/z): 209 (MN). s 7.4.333 (B) -b-amino-2-methyl-3-oxo-4H- l benz(and I, 2)oxazine 2-methyl-3-oxo-4H-benz | 1,4 |oxazine is obtained as a result of hydrogenation of (K)-2-methyl-b- and -nitro-3-oxo-4H-benz I, 4|oxazine. "H NMR (M5O-46); 5 6.60 (y, 1H), 6.12 (t, 2H), 4.40 (8, IN), 1.32 (d, ZNU ; LC/MS: purity: 100 95: MS (m/z): 179 (MH). 7.4.334 7-amino-4,4-dimethyl-1,3-dioxo-2NAN- The material is prepared according to to the method described in the journal ./. May Slet 2002, 45(163, isoquinoline 3394-3405. so 7.4.335 (2)-2-(2-hydroxystyl)-6-nitro-3-oxo-De solution of 2-amino-4-nitrophenol (16.5 d) in DMF (100 ml) at 0 "C, 4H-benzene 1,4 oxazine solid 9595 MaN (3 g) is immediately added. The reaction mixture is stirred at 0 "C for 20 minutes, then at room temperature for 1 hour Add 2-bromobutyrolactone (13.8 ml) to the reaction mixture and heat with a reflux condenser at 85°C overnight. The reaction mixture is concentrated to about 25 mL and diluted with 25 mL of MeOH. With stirring, 400 ml of deionized water is poured in, and the precipitate is collected by filtration and dried in a funnel for 4 hours to obtain (g)-2-(2-hydroxyethyl)-b-nitro-3-oxo-4H-benzi I,4|oxazine . "NN NMR (0M50-96): 6 7.82 (46.18), 7.75 (4.10, 718(y, 1), 4.90 (pu, 18), 4.70 (y, IN ), 3.8 (t, 2H), 1.96 (t, 2H); LC/MS: purity: 100 55; MS (m/z): 239 (MN). 7.4.336 (t)-b- amino-2-(2-hydroxyethyl)-3-oxo-Solution (-)-2-(2-hydroxyethyl)-6-nitro-3-oxo-4H-benzi 1,4 |oxazine (1 g) In EUB/ EUAsC

AN-benz 1, Jaoxazin (160 mg; 1:1 by volume) is hydrogenated under a pressure of 3.4 atm in the presence of 200 mg of 1095 PYS (Verivva) to obtain (--)-6-amino-2-(2- Hyloxyethyl)-3-oxo-4H-benzi1,oxazine. /N

NMR (РМ5О-46): 5 6.60 (4, 1H), 6.12 (t, 2NU, 4.58 (i, 1H), 4.40 (t, IN), 3.57 (ti, 29 ), 1.76 (t, 2NU; LC/MS: purity: 98 90; MS (m/z): 209 (MH) 7.4.337 48)-2-chloro-5-fluoro-Ma-(2-methyl -3-oxo- Analogously to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, 4H-benz|1,oxazin-b-yl)-4-(5)-2- chloro-5-fluoro-Ma-(2-methyl-3-oxo-4H-benz 1, Poxazin-b-yl)-4-pyrimylinamine pyrnmidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and (5) -b-amino-2-methyl-3- oxo-4H-benzi | 4| oxazine. "NYAM? (0M50-46); 5 8.2 (4, IN), 7.21 (t, 2H)) 6.95 (9, 1H), 4.62 (d, 1NU, 1.41 (y, ZNU; LC/MS: purity; 96 96; MS (m/z): 309 (МН. 7.4.338 M2- chloro-5-fluoro-M4-(2-(E)-methyl -1,4- benzoxazin-3-na-6-yl)-pyrimidinamine 7.4.339 (E)-2-chloro-5-fluoro-M4- (2-methyl-3-oxo- | Similar to the preparation of 2-chloro-M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, 4H-benz(1,oxazin-b-yl)-4- ( K)-2-chloro-5-fluoro-M4-(2-methyl-3-oxo-1H-benz| I Doxazin-b-yl-4-pyrimidinaminium pyrimidinamine is obtained as a result of re actions of 2,4-dichloro-5-fluoropyrimidine and (K)-6-amino-2-methyl-3"oxo-4H-benzyl!,4|oxazine. "N.NMR (0M50-46): 5 8.2 (a, 1H), 7.21 (t, 2H), 6.95 (4, 18), 4.62 (9, 1NU, 1.41 (a, ZNU; LC/LMS: purity: 96 25; MS (m/i): 309 (MN). 7.4.340 (y)p-2-chloro-5-fluoro-M4-(2402- Analogous to the preparation of 2-chloro- M4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, hydroxyethyl)-3-oxo-4H- (nne-chloro-5-fluoro-M4-12-(2-hydroxystyl)-3-oxo- 4H-benzi I Aoxazine-b-1l|-4-benz i, 4foxazin-b-yl|-4-pyrimidinamine|pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and ()-6-gamino-2 -(2-hydroxyethyl)-3-oxo-4H-benz|1,4|oxazine. "H NMR (OM5O-46): 5 8.2 (y, IN), 7.22 (t, 2H), 6.95 (y, IN), 4.60 (t, 18), 3.56 (t, 2H), 1.87 (t, ZNU; RH/MS: purity: 94 95;

MS (m/z): 339 (MN). 7.4.341 2-chloro-Ма-(4,4-dimethyl-1,3-dioxo-) Similar to the preparation of 2-chloro-М4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, 2НАН-zoquinoline 7 -yl)-5-fluoro-4-2-chloro-Ma4-(4,4-dimethyl-1,3-dioxo-2H.4H.isoquinolin-7-yl)-5-fluoro-4-pyrimidinamine pyrimidineamine is obtained in as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 7-amico-4,4-dimethyl-?2НА4Н.1,3-dioxoisoquinoline. "H NMR (0M50-46): δ 8.38 (y, IN), 8.05 (t, 2), 7.78 (a, 1), 1.47 (8, 6Н;); LC/MS : purity: 94 95; MS (m/z); 335 (MH). sem : PO - rons 7.4.342 (5)-5"fluoro-M2-(3-(M-) Similar to the preparation of M4-(3,4 -ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-He) methylamino)carbonylmethyleneoxyphenyl|-|pyrimidinediamine, (5)-5-fluoro-M2-|3-(M-methylamino)carbonylmethyleneoxyphenyl| -MM-(2-

M442-methyl-3-oxo-4H-methyl-3-oxo-4H-benz|1,oxazin-b-yl)-2,4-pyrimidinediamine is obtained as a result of benzyl-1,oxazin-b-yl)-2,4- reactions of (5)-2-chloro-5-fluoro-M4-(2-methyl-3-oxo-AN-benz| aniline, "I NMR (PM5O-46): δ 8.04 (d, 1H), 7.23 (t, 4H), 7.04 y, 1), 6.92 (y, 1), 6.53 (ai, 1), 4.61 (a, 2), 4.37 (5, 2H), 2.61 (d, ZN), 1.49 (y, ZN); LC/MS: purity: 96 95 MS (m/z): 453 (MH) (se) 74343 Ma-(4,4-dimethyl-1,3-dioxy-2NAN- Analogous to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2 -(3-hydroxyphenyl)-2,4-isoquinolin-7-yl)-5-fluoro-Mm2-/3-4(M-pyrimidinediamine, M4-(4,4-dimethyl-1,3-dioxo-2H). 4H-isoquinolin-7-yl)-5-fcor-M2-(3-0M- (22) methylamino)carbonylmethylenedioxypheni | methylamino)carbonylmethylenedioxyphenyl)-2,4-pyrimidinediamine is obtained as a result of p|-2,4-pyrimidinediamine (K909318 ) reactions of 2-chloro-Ma-(4,4-dimethyl-1, 3-dioxo-2H,4H-isoquinolin-7-yl)-5-fcor-4-che pyrimidineamine and 3-(h-methylamino rbonylmethyleneoxy)aniline. "H NMR (0М50-46): δ 8.30 (44, 15), 8.18 (t, 28), 7.98 (t, EN), 7.62 (4, 18), 7.38 ( 5, IN), 7.228, 18), 7.04 (i, 18), 6.43 (ad, 181), 4.24 (5, 2H), 2.61 (8, ZNU, 1.44 (5 , 6H); LC/MS: purity: 9225; MS (m/z): 479 and -(M- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- methylamino)carbonylmethyleneoxyphenyl|. | pyrimidinediamine, (K)-5-fluoro-Y42- Y3-(Mi -methylamino)carbonylmethyleneoxyphenyl|-Ma-(2-

Mma-(2-methyl-3-oxo-4H-methyl-3-oxo-4Hbenz 1 4 oxazin-b-1l)-2,4-pyrimidinediamine is obtained as a result of benzi 1,Doxazin-6b-yl)-2,4 - reactions of (K)-2-chloro-5-fluoro-Ma4-(2-methyl-3-oxo-4H-benz| 1 4oxazin-b-yl)-4-pyrimidinediamine (2909317) pyrimidineamine and 3-(M- methylaminocarbonylmethyleneoxy aniline. "H NAM? (OM5O-4a6u: b 8.04 (4, 1H), 7.23 (t, 4H), 7.04 (IN), 6.92 (d, 1H)), 6, 53 (ad, 1H), 4.61 (bd, 2H1), 4.37 (5, 2H), « 2.61 (9, ЗН), 1.40 (y, ЗН); LC/MS: purity: 96 95; MS (m/z): 453 (MH. 7.4.345 M2-(3-chloro-4-hydroxy-5-methylphenyl)» Analogous to the preparation of M4-(3,4-styrenedioxyphenia)-5-fluoro-M2 -(3-hydroxyphenyl)-2,4- shsh

M4-(4-dimethyl-1,3-dioxo-2NAH-pyrimidinediamine, M2-(3-chloro-4-hydroxy-5-methylphenyl) M444,4-dimethyl-1,3-dioxo-s isoquinoline-7- 1l)-5-fluoro-2,4-2H.anH-isoquinoline-7-ip)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction 2-pyrimidinediamine (K909320) chloro-M4-(4,4 -dimethyl-1,3-dioxo-2NA H-isoquinoline-7-1l)-5-fluoro-4-pyrimidinamine and 3- in! with" chloro-4-tihydroxy-5-methylaniline. Н NMR (0М50-46): δ 8.22 (0, 1Н), 8.19 (4, 180), 8.02 (44, " 18), 7.62 (t, ZEO, 1.50 ( 5, 6H); LC/MS: purity: 9295; MS (m/z)y: 456 (MAG). 74346 (5)-M2-4(3-chloro-4-methoxyphenyl)-5-fluoro- | Similar preparation M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M24(3-hydroxyphenyl)-2,4-

M4-(2-methyl-3-oxo-4H-pyrimidinediamine, (5)-M2-4(3-chloro-4-methoxyphenyl)-3-fluoro-M4-4(2-methyl-3-oxo-4H- benzo| and, Zoxazin-6-yl)-2,4- benzo/1,oxazin-6-yl)-2,4-pyrimidinliamine are obtained as a result of the reaction of (5)-2-chloro-5-(ee)pyrimidinediamine ( 2909321) fluoro-m4-(2-methyl-3-oxo-4H-benz| 1,4 |oxazin-b-yl)-4-pyrimidinamine and 3-chloro-4-methoxyaniline, "H ЯМ? (0M50-66): 5 8.12 (41, 741 (ad, 1), 7.22 (t. ZN), 6.97 (t,

F IN), 4.61 (d, IN), 3.78 (5, ZN)), 1.40 (y, ZN); LC/MS: purity: 97925; MS (m/z): 430 (MN). -y (Se) 42) ko 60 b5

7.4.347 (8)-M2-(3-chloro-4-methoxyphenyl)-5-fluoro- | Similar to the tattoo M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-

Ma-(2-methyl-3-oxo-4H-pyrimidinediamine, (K.)-M2-(3-chloro-4-methoxyphenyl)-5-fluoro-Ma-(2-methyl-3-oxo-4H-benzi) I, oxazin-b-yl)-2,4- benzyl 1,4 |oxazin-6-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction (K)-2-chloro-5-pyrimidinediamine (8909322) fluoro- M4-(2-methyl-3-oxo-4H-benz|1,4|Ooxazin-6-yl)-4-pyrimidinamine and 3-chloro-4-methoxyaniline. "H NMR (0M50-46): 5 8.12 (8, 18), 7.41 (dd, IN), 7.922 (t, ZN), 6.97 (t, 18), 4.61 (9, 160, 3.78 (z, ZNU, 1.40 (d, ZN); LC/MS: purity: 9795; MS (m/z): 430 (MN). 7.4.348 M24(3,5-dimethoxyphenyl) -Ma4-(4,4- Analogous to the synthesis of M4-(3,4-styrenedioxyphenium)-5-fluoro-M2-(3-hydroxyphenyl)-2,4" dimethyl-i,3-dioxo-2H,.4H-isoquinoline -7- |pyrimidinediamine, M2-(3,5-dimethoxyphenyl)-144-(4,4-dimethyl-1,3-dioxo-?H,4H-isoquinolin-yl)» 5-fluoro-2,4- pyrimidinediamine 7-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4-(4,4- (8909323) dimethyl-1,3-dioxo-2H.4H-isoquinoline-7-1l )-5-fluoro-4-pyrimidinamine and 3.55 dimethoxyaniline. "H YAMER (OM5O-4a6): 5 8.18 (y, 18), 8.05 (t, ZNU, 7.75 (t,, ZNU , 3.30 (5,

EN), 1.52 (5, 6NU; LC/MS: purity: 9195; MS (m/z): 452 (MN"). 7.4.349 (5)-М2-(3,5-dichloro-4- methoxyphenyl)-5- Similar to the synthesis of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-fluoro-M4-(2-methyl-3-oxo-4H-benzi1, 4)-| pyrnimidinediamine, (5)-M2-(3,5-dichloro-4-methoxyphenyl)-5-methyl-4-(2-methyl-3-oxo-4H-oxazin-b-yl)-2, 4-pyrimidinediamine benzol,41-oxazin-6-1l)-2,4-pyrimidinediamine is obtained as a result of the reaction of (5)-M2-chloro- (K908946) 5-fluoro-M4-4(2-methyl-3- oxo-4H-benz|1,Moxazin-6-1l)-4-pyrimidinamine and 3,5-dichloro-4-methoxyaniline. "NN NMR (2M5O0-46): 5 8.07 (4, 1H), 7.78 ( 5, 2H). 7.09 (t, 2H), 6.95 (0, 1), 4.61 (4, 1H)), 3.75 (5, ЗН), 1.21 (y, ЗН); LC/MS: purity: 9895; MS (m/z); 465 (MN). 7.4.350 (К)АМ2-(3,5-dichloro-4-methoxyphenyl)-5- Similar to the synthesis of IM4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-(3-hydroxyphenyl)-2,4- fluoro-M44(2-methyl-3-oxo-4H-benzi1,4)- | pyrimidinediamine, (K)-M2-(3,5-dichloro-4-methoxyphenyl)-5-fluoro-M4-(2-methyl-3-oxo-4H-oxazin-b-yl)-2,4-pyrimidinediamine benzyl 1,4|-oxazin-b-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction (B)-M2-chloro- (8908947) Z-fluoro-M44(2-methyl-3-oxo-4H-benz I oxazine-b-yl)-4-pyrimidinamine and 3,5-dichloro-4-methoxyaniline. "H NMR (PM5O-46): δ 8.07 (4, 1), 7.78 (5, 2), 7.09 (t, 2H), 6.95 (0, 18), 4.61 ( 4, 180), 3.75 (5, ZN), 1.21 (0, ZN); LC/MS: purity: 9895; MS (m/zu: 465 (МН. 7.4.351 (33-М2-( 3,5-dimethoxyphenyl)-5-fluoro-М4- 3-oxo-4H» pyrimidinediamine, (43-142-(3,5-dimethoxyphenyl)-5-fluoro-M4-(2-(2-hydroxyethyl)-3-oxo-4H-benz I, oxazin-6-yl |-24-benzyl!4oxazin-6-yl|-2,4-pyrimidinediamine is obtained as a result of the reaction M2-chloro-5-pyrimidinediamine (2908950) fluoro-Ma4-(2-(2-tihydroxyethyl)-3-oxo-4H -benzi 1,4 oxazin-6-yl|-4-pyrimidinamine and 3,5-dimethoxyaniline. "H NMR (OM5O-46): 65 8.04 (4, IN), 7.23 (t, 2H), 6.95 (t, ZN), 6.02 (t, 1H), 4.58 (t, IN), 3.50 (t, 7H), 1.90 (n, 28); LC/MS: purity : 9595; MS (m/z): 456 (MN). 7.A.352 (3)-M2-(3-chloro-4-methoxyphenial)-5-fluoro- | Similar to the preparation of M4-(3,4- ethylenedioxyphenia)-5-fluoro-yh2-(3-hydroxyphenyl)-2,4-1h4-(24(2-hydroxyethyl)-3-oxo-4H»pyrimidinediamine , (CE)-M2-(3-chloro-4-methoxyphenyl)-5-fluoro-M4-(2-(2-hyproxyethyl)-3-oxo- benzyl (HP.4|oxazin-6-yl)-2, 4- 4H-benz| And ,4|oxazin-6-yl-2,4-pyrimidinediamine is obtained as a result of the reaction M2-chloro-5-pyrimidinediamine (K908951) fluoro-M4-(2-(2-hydroxyethyl)-3-oxo-4H-benzi 14 |oxazin-6-yl|---pyrimidinamine and 3-Ha chloro-4-methoxyaniline. "H NMR (0M50-46): δ 8.04 (4. 18), 7.80 (t, 18), 7.41 (t, 1H), 7.20 (t, 2NU, 6.97 (t, 2H), 4.61 (yv, IN, 3.73 (5, ЗН), 3.50 (t, 2H), 1 ,90 (t, "NU; LC/MS: Ge) purity: 9395; MS (m/z): 460 (MH). 7.4.353 (5,5)-M2,M4-bis-(2-methyl- 3-oxo-4H- Similar to the preparation of M4-(3,4-ethylenelioxyphenyl)-5-fluoro-42-(3-hydroxyphenyl)-2,4- benzyl 1,4)oxazin-6-yl)-5-fluoro- 2,4-pyrimidinediamine, (5,5)-142,M4-bis-(2-methyl-3-oxo-4H-benz/1,4|oxazin-6-yl)-5-fluoro-2,4- pyrimidinediamine (К908952) pyrimidinediamine is obtained as a result of the reaction of (5)-2-Hnpor-5-fluoro-M44(2-methyl3»oxo-4H-benzii,CHoxazin-b-yl)-4-pyrimidinamic and (5)-6- Amino-2-methyl-4H-benz| 1,4 | oxazine. (Che) "H МАМ? (0M50-yb): 6 8.04 (4, 18), 7.23 (t, 2H), 7, 15 (t, IN), 7.04 (t, IN), 6.92 (t, 2H), 4.58 (t, 2H), 1.38 (t, 6H); LC/MS: purity a: 9595; MS (m/z): 451 (MN). b 7.A.354 (5)-M2-(3,5-dimethoxyphenyl)-5-fluoro-Ma. | Analogous to the preparation of m4-4(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- (2-methia-3-oxo-4H-benz| 1,4|oxazine-b- pyrimidinediamine, (5)-M2-(3,5-dimethoxyphenyl)-5-fluoro-M4-(2-methyl-3-oxo-4H»yl)-2,4-pyrimidinediamine (K908953) benz 1,4 | oxazin-6-yl)-2,4-pyrimidinidiamine is obtained as a result of the reaction (5)-M2-chloro-5-h-fluoro-M4-(2-methyl-3-oxo-benzi 1,4 |oxazine-b- yl)-4-pyrimidinamine and 3,5-dimethoxyaniline. "H NMR (PM5O-46): 8 8.04 (0, 1H), 7.23 (t, 1), 7.19 (t, 1), 6.95 (t, sem

ЗН), 6.05 (t, 1Н), 4.61 (4, 1Н), 3.60 (5, 6Н), 1.40 (y, ЗН); LC/MS: purity: 9805; MS (m/z):

Z5 426(M). so 7.4.355 (K)-M2-(3,5-dimethoxyphenyl). 5-fluoro-M4- | Similarly to the preparation of IM4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- (2-methyl-3-oxo-4H-benz|1,4)oxazine-b- | pyrimidinediamine, (K.)-M2-(3,5-dimethoxyphenyl)-5-fluoro-M4-4(2-methyl-3-oxo-4H.yl)-2,4-pyrimidinediamine (K908954), benz( 1 ,4 |oxazin-6-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction (K)-M2-chloro-5-fluoro-Ma-(2-methyl-3-oxo-benz| 1, oxazine-b- yl)-4-pyrimidinamiva and 3,5-dimethoxyaniline. /"H NMR (0M5O-46u; δ 8.04 (8, EN), 7.23 (p, IN), 7.19 (p, 1H)), 6.95 St, «

ZNU 6.05 (ti, 18), 4.61 (4, 1H), 3.50 (5, 61), 1.40 (d, ZNU, RH/MS: purity: 98995; MS (mi); 426 (МН. 50 7.4.356 142-(3,5-dichloro-4-methoxyphenia)-Ма-(4,4- | Similar to the synthesis of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-(3- hydroxyphenyl)-2,4- with dimethyl-|,3-dioxo-2H,4H-isoquinoline-7-|pyrimidinediamine, M2-(3,5-dichloro-4-methoxyphenyl)- M4-(4,4-dimethyl -1,3-dioxo-2H.AN-1yl)-5-fluoro-2,4-pyrimidinediamine isoquinoline 7-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction M2-chloro-M4-h ( K908955) "4,4-dimethyl-1,3-dioxo-?7H, I H-isoquinolin-7-yl)-5-fluoro-4-pyrimidinamine and 3,5-dichloro-4-a methoxyaniline. "H NMR (OM5O-46): 6 8.22 (d, IN), 8.20 (4, TE, 8.02 (49, 1H), 7.62 (t,

ZNU, 3.75 (in, ZN), 1.50 (5, 6H); LC/MS: purity: 9295; MS (m/z): 491 (MN. 7.A.357 1х4-(4,4-dimethyl-1,3-dioxo-2H,4H. Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro -M2-(3-hydroxyphenyl)-2,4-isoquinolin-7-yl)-M2-(indazol-b-1l)-5-pyrimidindiamine, M4-(4,4-dimethyp-|,3-dioxo-2H ,4H-isoquinoline-7-1l)-M2-(indazol-b-yl)-5-bo fluoro-2,4-pyrimidinediamine (2998956) fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M2-chloro-M4- (4,4-dimethyl-1,3-dioxo-2H,4H-isoquinoline-7-1l).5-fluoro-4-virimilinamine and b-aminoindazole. H NMR (DM50-46); 5 5.28 (t, 2H ), 8.17 (t, NI), 8.05 (t, 2H), 7.95 (5, 1), 7.62 (t, ZNO, 7.23 (t, ko -y (Se) 42 ) ko 60 b5 now 18), 1.48 (z, 6H); LC/MS: purity: 9595; MS (m/z): 432 (MH). 7.4.358 Ma-(3,3-dimethyl-4H -benzi 1,4|oxazine-6- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-ip)-M24(3,5-dimethylphenyl) --5-fluoro-2,4-pyrimidinediamine, M4-(3,3-dimethyl-4H-benz|1,4)oxazin-b-yl)-M2-(3,5-dimethylphenyl)--5-pyrimidinediamine (K908586) fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M2-chloro-M4-(3,3-dimethyl-4H-benz(1,oxazin-b-yl)-5-fluoro-4-pyrimidinamine and 3,5-dimethylaniline). "H NMR (0M5O- 2 46): 58.02 (9, 1H), 7.21 (t, 2H), 6.80 (t, 1NU, 6.77 (t, 1H), 6.60 (t , 1H), 6.50 (t, 1NU, 3.75 (5, 20, 2.15 (8, 6H), 1.15 (5, 6H); LC/MS: purity: 9592; MS (m/ z): 394 (MIN). 7.4.359 M2-(3-chloro-4-methoxyphenyl)-M4-(3,3- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-142-(3 -hydroxyphenyl)-2,4-dimethyl-4H-benzoic acid 1,4-ixazin-6-yl)-5-pyrimidinediamine, M2-(3-chloro-4-meoxyphenyl)-M4-(3,3-dimethyl-4H-benzoic acid) 1,4Ixazin-b-yl)" fluoro-2,4-pyrimidinediamine (K908587) 5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of M2-chloro-M4-(3,3-dimethyl-4H-benzhy, Zoxazine -b-yl)-5-fluoro-4-pyrimidinamine and 3-chloro-4-methoxyaniline. ), 7.58 (t, 1H), 6.97 (t, 1NU, 6.80 (ha, 2H), 6.60 (t, 1H), 3.77 (5. ZNO, 3.74 (5 , 2H), 1.15 (5, 6H); LC/MS: purity: 9495; MS (m/z); 430 (MH). 7.4.360 M4-(3,3-dimethyl-1,4-benzoxazine -b-yl)- Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenial)-2,4-5-fluoro-M2-(indazol-b-yl)-2, 4- pyrim ylindiamine, M4-(3,3-dimethyl-1,4-benzoxazin-b-yl)-5-fluoro-M2-(indazol-6-yl)-2,4-pyrimidinediamine (K908591) pyrimidineliamine is obtained as a result of the reaction of Mi2-chloro -M4-(3,3-dimethyl-4H-benz(1,oxazin-b-yl)-5-fluoro-4-pyrimidicamine and b-aminoindazole. /"H NMR (OM5O-46): 58.19 (5, IN), 8.03 (4, INU, 7.91 (5, 1), 7.58 (t, 180), 7.22 (t , TN), 6.97 Et, IN), 6.84 (t, 1), 6.64 (t, 1H), 3.77 (5, 2H), 1.15 (5, 6NU; LC/MS: purity : 9295; MS (m/z): 406 (Mn. 7AZ Ma4-(3,3-dimethyl-4H-benz(I, 4|oxazine-b- | Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5 -fluoro-M2-(3-hydroxyphenyl)-2,4-yl)-5-fluoro-Mm2-(MI-methylindazol-b-yl)-pyrimidinediamine, M4-(3,3-dimethyl-4H-benzi 1, 4) oxazin-6-yl)-5-fluoro-H2-(M1-2,4-pyrimidinediamine (K9085972) methylindazol-b-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of M2-chloro-M4-(3 ,3- dimethyl-4H-benz/1,4|oxazin-6-yl)-5-fluoro-4-pyrimidinamine and b-amino-MI.methylindazole. "H NMR (0M50-y6): 6 8.16 (5, 1), 8.08 (4, 18), 7.90 (5, 1H), 7.22 (t, 1H), 7.22 (t, 1H), 6.97 (t, 2H), 6, 64 (t, 1H), 3.80 (v, ЗН), 3.77 (v, 2H), 1.15 (5, 6H); LC/MS: purity: 9392; MS (m/zu: 420 ( 7.4.362 Salt of toluenesulfonic acid (K)-M2-(3-. | Similar to the preparation of the salt of p-toluenesulfonic acid M2-(3,5-dimethoxyphenyl)-M4-(2,2-chloro-4-m ethoxyphenyl)-5-fluoro-Ma-(2-dimethyl-3-oxo-4H-benzi 1,4|oxazine-b-1l)-5-fluoro-2,4-pyrimidinediamine, p-methyl-3-oxo salt -4H-benzi 1,4 |oxazin-b-yl)". | toluenesulfonic acid (K)-M2-(3-chloro-4-methoxyphenyl)-5-fluoro-M4h(2-methyl-3-oxo-4H-2,4-pyrimidinediamine (908580) benz|1,Jaoxazin-b-yl )-2,4-pyrimidinediamine is obtained as a result of the reaction (K)-M2-(3-chloro-4-methoxyphenyl)-5-fluoro-M4-(2-methyl-3-oxo-4H-benzi 1,2 |oxazine -b-yl)-2,45 pyrimidinediamine and p"toluenesulfonic acid monohydrate,

I Adverb of aminoindazolines with 7.4.363 1-(2-ethoxycarbonylethyl)-5- Analogously to the preparation of 1-(methoxycarbonylmethyl-5-nitroindazoline, 142- nitroindazoline and 2-(2- ethoxycarbonylethyl)-5-nitroindazoline are obtained as a result of the alkylation reaction 5 - Ge) ethoxycarbonylethyl)-5-nitroindazoline of vitroindazoline with ethyl 3-bromopropionate in the presence of KSO". 1-4022- ethoxycarbonylethyl)-5-nitroindazoline (4395) with a high CI value on TLC in 3092

EUAsn-hexanes are collected by purification using the method of column chromatography on silica gel. "H NMR (SOSI): 6 8.70 (4, IN, 1- 1.7 St), 8.27 (46, 1, 1- 2.3 and 8.8 Hz), 5.20 (a IN , 75 1.7 Hz), 7.59 (I, 1H, 1-88 Gy), 4.70 0, 2H, 1- 6.4 Gy), 4.07 (di, 2H, 1 7.0 Gy ), 3.01 (6 2H, 1-64 Gy), 1.16 (i, ЗН, 2-5 7.0 Hz). A by-product with a low KE value, 24(2- (Ce) ethoxycarbonylethyl)-5 -nitroinnazoline is also collected by eluting the 5095 column

EC with Asn-hexanes. "H NMR SOS): 5 8.71 (y, IN, 3-2.0 Gy), 8.32 (5, 1), 8.08 (arr ay, (e") 1H. 3-25 and 9 ,7 Hz), 7.73 (40, 1H, 12 0.8 and 9.7 Hz), 4.77 (6 2H, 12 6.4 Hz), 4.12 (di, 7H,3- 70 Hz )" 3.08 (, 2H, 3: 6.4 Hz), 1.22 (6, ЗН, 7" 7.0 Hn). "- 7.4.364 5-amino-1-2- Similar to the reduction of distillate 2 -methyl-2-(3-nitrophenoxy)maponate, 1-(2-ethoxycarbonylethyl)indazoline ethoxycarbonylethyl)-5-nitroinlazoline is reduced to obtain 5-amino-1-(2-ethoxycarbonylethyl)indazoline, "H NMR (SOCI") : 6 7.78 (5, | H), 7.30 (a, 1H, 1- 8.8 Hz and 6.91 (4, IN, 1- 2.3 Gy), 6.87 (44, 1H, 7- 2.3 and 8.8 Gy), 4.59 (i, 2H, 3- 6.4 Hz), 4.08 (d, 2H, 12 7.0 Hyd, 3.02 (bg 5, 2H ), 2.92 (1, 2H, 3-- 7.0 Hu, 1.16 (i, ZY, 7- 7.0 Gy). (ee) 7.4.365 5-amino-2-(2- Similarly reduction of distillate 2-methyl-2-(3-nitrophenoxy)malonate, 2-(2-ethoxycarbonylethyl)indazoline ethoxycarbonylethyl)-5-nitroindazoline is reduced to obtain 5-amino-2-(2-ethoxycarbonylethyl)indazoline. "NN NMR ( SRSI;): 6 7.64 (5, 1H), 7.45 (40, 1H, 7-0.9 and 9.1

Gy), 6.74 (va, 1H, 12 2.0 and 9.1 Gy), 6.670, 1H, 1-20 Go), 4.57 (6, 2H, 12 6.7 Hz), 4.05 (in 2H, 1- 7.0 Hz), 3.28 (bg 5, 2H), 2.93 (i, 2H, 1- 6.7 Hz), 1.16 (, ЗН, - 7.0 Gm ). "7.4.366 1-Methyl-6-nitroindazoline and 2-methyl-6- Similarly to the preparation of 1-(methoxycarbonylmethyl)-5-nitroinnazoline, the alkylation reaction of b-nitroindazole with methyl iodide in the presence of K.SO" is carried out. After the completion of the reaction, the reaction mixture is diluted with water. The formed solid is filtered, dried and subjected to chromatography on silica gel using 157 and ECHOAc:p-n-hexanes to obtain a product with a high value of B | -methyl-b- and - nitroindazoline. Yin YaMe (SOS): 5 8.32 (5, IN), 8.10 (5, IN), 8.01 (ai, 1, 2.7 and 8.8

Hz) 7.83 (4, 1H, 34-8.8 Hz), 4.18 (5, 30). A byproduct with a low BH value, 2-methyl-b-nitroindazoline, is also collected by washing the 3095 BO column with Ac:n-hexane. "H NMR (SOCI,): 5 8.69 (y, IN, 1 2.0 Hz), 8.03 (5, 18), 7.90 (94, 1H, 12 2.0 and 9,!

Go), 7,758, 1H,. 1-9 Hz), 4.31 (5.13N). (ee) 7.4.367 b-amino-1-methylindazoline Similar to the reduction of diethyl 2-methyl-2-(3Z-nitrophenoxy)malonate, b-amino-1-methylindazoline is obtained as a result of the reduction of 1-methyl-b-nitroinlazoline. "H NMR with (Srsv): 8 7.80 (5, 1NU, 7.48 (44, IN, p- 0.6 and 8.2 G in), 6.58 (49, 1Н, 3 1.8 and 8.2 Hn), 6.54 (8, -th 7 42) ko 60 b5

GO domov zecezna zas 7.A.368 b-amino-2-methylindazoline Similarly to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, b-amino-2-methylindazoline is obtained as a result of the reduction of 7-methyl-b-nitroindazoline . "H NMR (HOS 7.71 (v, 1), 7.43 (4, 18, )1- 8.85 Gy), 6.79 (arr a, IN, 7- 1.7 Gy), 6.58 ( 4d, IN, 3- 1.7 and 8.8 Hyd, 4.11 (8, ZNI), 3.31 (Bg5, 2H). 7.4.369 2-chloro-5-fluoro-Ma4-(4-fluoro -3- Similar to the preparation of 2-chloro-M4-(3,4-ethylenethiooxyphenyl)-5-fluoro-4-pyrimidinamine, methoxyphenyl)-4-pyrimidinamine 2-chloro-5-fluoro-M4-(4-fluoro-3- methoxyphenyl)-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-fluoro-3-methoxyanil. ,31 (4, 1, 1- 3.5 Go), 7.54 (49, IN, 3-: 8.2 Gy), 7.30-7.17 (t, 2H), 3.81 (5 , ZN).

LC/MS: retention time: 12.11 min.; purity: 9895; MS (m/z): 272 (MN). 7.4.370 2-chloro-M4-(4-chloro-3-fluorophenia)-5- Similar to the preparation of 2-chloro-M4A-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, fluoro-4-pyrimidinamine 2-chloro-m4-(4-chloro-3-fluorophenyl)-5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 4-chloro-3-fluoroaniline. /"H NMR (OM5O0-46): 810.25 (5,

IN), 8.39 (y, IN, 3» 3.5 Gu, 7.87 (89, 1H, 3-18 and 11.4 Gy), 7.59 (t, 1NU, 7.09-6.38 ( t, 18),

PH/MS: retention time: 13.74 min.; purity: 935; MS (m/z): 277 (MN). 743 2-chloro-M4-(3-chloro-4-fluorophenyl)-5- Similar to the preparation of 2-chloro-M4-(3 4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidinamine, fluoro-4-pyrimidinamine 2-chloro -MA-(3-chloro-4-fluorophenyl)-5-fluoro-4-pyrimidinamine is obtained as a result of the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-chloro-4-fluoroaniline. "H NMR (0M50-46): 5 10.12 (5, 1NU 8.355, 1), 7.93 (44, IN, 1- 2.6 and 7.6 Hz), 7.69-7.64 ( t, 1H), 7.43 (, 1H, 3- 9.2 Gy).

PH/MS: retention time: 13.38 min.; purity: 9195: MS (m/5): 277 (MN). 74372 44(2,6-dimethoxypyrid-3-yl)» M2-(14(2- Similar to the preparation of Ma-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- ethoxycarbonylethyl )indazolin-3-yl)-5-pyrimidinediamine, M4-(2,6-dimethoxypyrid-3-1d)» M2-(1-4(2-ethoxycarbonylethyl)indazolin-5-fluoro-2,4-pyrimidinediamine (KU35381 )yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M-(2,6-dimethoxypyrid-3-yl)-5-fluoro-4-pyrimidinamine and 5-amino-I-( 2-stoxycarbonylethyl)indazoline. "H NMR (YUM5O0-46): 5 9.08 (z, IN), 8.68 (5, 1), 8.00 (d,

IN GI), 7.93 (5, 1H), 7.74 (4, IN, le 8.2 g), 7.67 (5, 1NYU), 7.42 (d, 1H, 72 9.4 Go ), 7.34 (d1Н,3- 9.4 Hz), 6.46 (y, IN, 2-82 Gy), 4.51 (6 2Н, 1-64 Г and), 3.96 (db, 2H, 3-7.0 Gy). 3.91 (5, 18), 3.83 (8, 1H), 2.85 (1, 2H, 1-: 6.4 Hz), 1.05 (i, ZN, 7: 7.0 Hz) . LC/MS: retention time: 10.94 min.; purity: 9095; MS (m/z): 482 (MN). 7.5.373 Mma-(4-chlorophenia)-5-fluoro-M2- 141-12-40. Similar to the preparation of MA-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-(M. methylamino)carbonylethyl |indazoline-2-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(4-chlorophenyl) -5-fluoro-yl)-2,4-pyrimidinediamine (KO35382) M2-414(2-4M-methylaminocarbonyl)ethyl|indazolin-5-cl)-2,4-pyrimidinediamine is obtained as a result of the reaction M4-(4-chlorophenyl )-M2-1Y (2-ethoxycarbonylethyl)indazolin-5-yl|-5-fluoro-2,4-pyrimidinedismine and methylamine hydrochloride, /H NMR (0M50-46): 6 9.44 (53, 1), sem 9.21 (8, IN), 8.11 (4, IN, 1-1 Hz), 8.07 (5, 1H), 7.85 (0, 2H, 15 9.4 g), 7, 82 (40, 2H, 3- 2.9 Ge) and 8.8 Hz), 7.52 (0, 1H, 3- 9.4 Hz), 7.46 (y, 1H, 2-82 Gy), 7, 34( IN, I 8.8 Gu, 4.53 ( 21, 1-7.0 Gy), 2.63 (6 2H, 1 7.0 Hz), 2.49 (y, ЗН, 2- 4, 7 Hn), LC/MS: retention time: 8.58 min.; purity: 9795; MS (m/z): 440 (MH). 7.4.374 Ma -(4-chlorophenyl)-5-fluoro-M2- 114 (3- Analogously to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-fluoro-ma-I4(2-hydroxy-1,1-hydroxypropylindazolinase-121-2,4»dimethylethyl)phenyl|-2,4-pyrimidinedia mine, M4-(4-chlorophenyl)-5-fluoro-M2-1-(3- (Te pyrimidinediamine (K935383) hydroxypropyl)indazolin-5-yl|-2,4-pyrimidinediamine is obtained as a result of the reaction M444-chlorophenyl)- M2-(1-(2-stoxycarbonylethyl)indazoline-5-1l|-5-fluoro-2,4-pyrimidinediamine with dibutyllithium aluminum hydryl. "H NMR (YUM5O-46): C 9.44 (is, 1NI), 9.20 (5, 183, VL (9, (e) 1H, 124.2 cis), 8.07 (5, 18) , 7.85 (4, 1H, 12: 9.4 Gy), 7.82 (04, ЗН, 1-29 and 8.8 Hz), 7.52 (4,

IN, 1-94 Gy), 7.46 (4, IN, 1- 9.4 Hz), 7.37 (y, 1H, 12 8.8 Gy), 4.56 (1, 1, 1- 5 ,2 Hz), 4.39 (i, «- 2H, 12: 6.4 Hz), 3.35 (arr d, 2H, 35 6.4 Hz), 1.93 (a, 2H, 12 6.4 Hz ). LC/MS: retention time: 8.85 min.; purity: 9695; MS (m/z); 413 (MN). 7. A375 MA-(3,4-difluorophenyl)-M2-| 1-(2- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-tihydroxyphenyl)-2,4-sethoxycarbovylethyl)inlazolin-5-yl|-5-pyrimidinediamine, M4- (3,4-difluorophenyl)-M2-11-(2-ethoxycarbonylethyl)indazolin-5-yl)-5-

From fluoro-2,4-pyrimidinediamine (935384) fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M-(3,4-difluorophenyl)-5-he) fluoro-4-pyrimidineamine and 5-amino- 1-(2-ethoxycarbonylethyl)indazoline. "H NMR (PM5O0-46u: 6 10.30 (5, 1H), 10.09 (5, 1H), 8.268, 1H, 7: 4.7 Gy), 7.95 (5, 1H), 7, 89 (5, 2H), 7.66 (y,

IN, 7» 8.8 Gy), 7.47-7.32 (t, ZN), 4.60 (i, 2H, 1- 6.4 Pi), 3.97 (Chi, ZN, 1 7, 0 Gy), 2.90 (.2H, 1- 6.4 Hz), 1.06 p, ЗН, 1- 7.0 Gy). PH/MS: retention time: 11.45 min.; purity: 969,

MS (m/z: 457 (MY). " 7.A.376 M4-(3,4-difluorophenyl)-5-fluoro-M2-11-12- | Similar to the preparation of MA-(3,4-ethylenedioxyphenyl)- 5-fluoro-Mm2-(34A-(M-methylaminocarbonyl)ethyl|indazoline-|methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3,4-difluorophenyl)-5» with 5-yl)|-2 ,4-pyrimidinediamine (KU35385) fluoro-m2-4 1420 U-methinaminocarbonyl)ethyl)indazolin-5-yl)|-2,4-pyrimidinedigmine c is obtained as a result of the reaction Ma4-(3,4-lifluorophenyl)-M2-11 -(2-ethoxycarbonylethyl)indazolin-5-yl1-5-fluoro-2,4-pyrimidinediamine and n-z" methylamine hydrochloride. "H NMR (0M5O0-46): δ 9.49 (5, 180), 9.27 (5, 10), 8.13 (y, IN, 2: 3.5 Hz), 8.08- and 8.00 (arr 5, 2H), 2.87 (5, 1), 7.83 (db, IN, Yak 4.7 p), 7.56-7.49 (t, ZN), 7.36 (d4, IN, I 8.8 and 20.1 Pi), 4.52 (1, ZN, 1 6.4 Hz), 2.63 (i, 7H, 1- 6.4 Gy), 2.59 (4, ZN, 1-47 Gy). LC/MS: retention time: 8.44 min.; Purity: 9605; MS (m/z): 442 (Mn. 7.4.377 ma-(3,4-difluorophenyl)-5 -fluoro-х2411-(3- Similar to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-fluoro-M4-|4(2-hydroxy-1,1-

Go! hydroxypropyl)inlazolin-5-yl1-2,4-dimethylethyl)phenyl|-2,4-pyrimidinediamine, M4-(3,4-difluorophenia)-5-fluoro-M2-(1-(3-pyrimidinediamine) (4935386) hydroxypropyl )indazolin-5-1l|-2,4-pyrmidinediamine is obtained as a result of the reaction of M4-(3.4-difluorophenyl)-M2-114(2-ethoxycarbonylethyl)indazolin-5-yl|-5-fluoro-2,4-co of pyrimidinediamine and dibutyllithium aluminum hydride.

9.26 (z, IN), 8.13 (4, 1H, 7" 3.5 Hz), 8.07-8.03 (arr 5, 2NI), 7.86 (z, 1H), 7.54- 7.45 (t, ZN), 7.33 (46, 18, 1-8.8 and 19.3 Hz), 4.56 0, 1H,2- 4.7 Si), 4.39 (B, 2H, 3-- 6.5 Gy), 3.35 (di, 2H, 12 6.5 Hz), 1.93 (4, 2H, 52: 6.5 Gy). LC/MS: retention time: 8.86 min.; purity: 9695; MS (m/z: 415(Mn. 7.4.378 4-(3,4-dichlorophenyl)-M2-|142- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl) )-2,4- 2 ethoxycarbonylethyl)indazolin-5-yl|-5"pyrimidinediamine, Ma4-(3,4-dichlorophenyl)-M24(1-(2-ethoxycarbonylethyl)indazolin-5-yl|-5- fluoro- 2,4-pyrimidinediamine (935389) fluoro-2,4-pyrimidinediamine is restrained as a result of the reaction of 2-chloro-1-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidineamine and 5-amine-1-(2- ethoxycarbonylethyl)indazodine. "H NMR (OM5O-46): δ 10.25 (5, 1H), 10.00 (5, 1), 8.27 (d, IN, 154.7 Go), 8.02 ( 5, 1), 7.95 (5, EN), 7.87 (5, 18), 7.72 (4, 1H,7- 8.8 Gy), 7.65 (4, 1H, )- 8.8 Hz), 7.52 (4, IN, 3- 8.8 Go), 7.35 (4, 1H, 2 8.8 Hn), 5.59 (1, 2H, 12: 5.4 Go), 3.97 (di, 24, 1-7.0 Ha), 2.90 (2A, 7-64 Hn), 1.06 (5 ZN, 1 7.0 Hz). RH/MS: duration of retention: 13 ,10 min.; purity: 9596; MS (m/z): 490 (MN. 7.A.379 M4-(3,4-dichlorophenyl)-5-fluoro-M2-11- Anaphogically to the preparation of M4-(3, 4-Stylenedioxyphenyl)-5-fluoro-M2-I3-(M-p methylamino)carbonylmethyleneoxyphenylI-2,4-pyrimi lindiamine, M4A-(3,4-dichlorophenyl)-5-methylaminocarboyl)ethyl||indazolin-5-fluoro-M2-11-H2(M-methylaminocarboni l)ethyl|indazolin-5-1l)-2,4-pyrimylindiamine Tl|-2,4-pyrimidineliamine (KU35390) is obtained as a result of the reaction of M4-(3,4-dichlorophenyl)-M2-H14(2-ethoxycarbonylethyl)indazolin-5-yl|-5-fluoro-2,4-pyrimidinediamine and methylamine hydrochloride. "YAN NMR (0M5O0-46): 6 9.55 (v, 1H), 9.28 (5, 1H), 8.15 (0, IN, 1- 3.5 Hn), 8.08 (y, IN, and: 2.3 Hz), 8.00 (5, NI), 7.86 (5, 1H), 7.80 (t, 2NI), 7.55-7.44 (t, ZN), 4.52 (i, 2H, 1-5 7.0 Gy), 2.63 (6 2H, 7 7.0 Gy), 2.50 (a, ЗН, 1- 4.7 Go). RHUMS: duration retention: 9.83 min.; purity: 9695; MS (m/z): 475 (MN). 7.A.380 7444(33,4-pichlorophenyl)-5-fluoro-M2-1443" Similar to the preparation of M2- (3,4-ethylenedioxyphenyl)-5-fluoro-Ma-|4(2-hydroxy-1,1-hydroxypropyl)indazolin-5-i1|-2,4-dimethylethyl)phenyl)|-2,4-pyrimidinediamine, M4-(3,4-dichlorophenyl)-5-fluoro-M2-11-(3-pyrimidinediamine (K935391) hydroxypropyl)indazolin-5-yl|-2,4-pyrimidinediamine is restrained as a result of the reaction of M4-

13,4-dichlorophenyl)-M2-|(1-(2-stoxycarbonylethyl)indazolin-5-yl|-5-fluoro-2,4-pyrimidinediamine and diisobutyllylium aluminum hydride. "H NMR (OM5O-46): 8 9.67 (5, IN), 9.38 (5, IN), 8.23 (4, 1H, 1: 3.5 Hz), 8.17 (arry, IN, 42: 2.3 Gy), 8, 08 (5, 1), 7.95 (5, 18), 7.87 (1, 7- 8.8 Hz), 7.62 (4, 1H, 1- 8.8 Gy), 7.59 - 7.53 (ha, 2H), 4.47 (2H, 1 6.4 Hz), 3.44 (arr. 2H, 12 6.4 Hz), 2.02 (а, 2H, 2- 6 .4 Gy), LC/MS: retention time: 10.31 min.; purity: 9595; MS (m/z): 448 (MH). 74381 M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2 Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-(1-methylindazolin-b-yl)-2,4-pyrimidinediamine, MA-(3 ,4-ethylenedioxyphenyl)-5-fluoro-M2-(1-methylindazolin-6-yl)-2.4-pyrimidinediamine (6935392) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M-(3,4-ethylenelioxyphenyl)-5-fluoro -4-pyrimidinamine and I-methyl-b-aminocnazole.'H NMR (0M50-a6): 5 10.40 15, 1H), 10.27 (5.1), 8.27 (8, 1H, 1- 4.7 Gy), 7.95 (v, 1H), 7.81 (v, 1H), 7.66 (6, IN, - 8.8 Hz) , 7.25- sem p 753 t, IN), 715-709, ZNU 6.77, NNI 88 o), 124-415 (t, 48), Z,B1 (5, ZNU. at

PH/MS: retention time: 9.19 min.; purity: 9790; MS (m/z): 393 (ME). 7.4.382 m4-(3,4-dichlorophenia)-5-fluoro-M241- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- methylindazolin-b -yl)-2,4-pyrimidinediamine, M4-(3,4-dichlorophenyl)-5-fluoro-M2-(1-methylindazolin-b-1l)-2,4-pyrimidinediamine (935393) pyrimidinediamine is restrained as a result of reaction 2 -chloro-M-(3,4-lichlorophenyl)-z-fluoro-4-pyrimidinamine and 1-methyl-b-aminoinlazole. I AM (OM0-46): 6 9.68 (in, 1NI), 9.56 (5, 1), 8.23 (4, 1H, 1-41 Si), 8.13 (4, 18, /- 2.3 Hz), 7.98 (5, T1H), 7.86 (5, 1H), 7.79 (ad, IN, 1- is e) 2.3 and 8.8 Gy), 7 .58 (4, IN, 7- 8.8 Hz), 7.53 (4, 1H, 3- 8.8 Hz), 7.22 (46, IN, 1- 2.3 and 8.8 Gy) , 3.77 (8, ZN). PH/MS: retention time: 13.48 min.; purity: 9795; MS (m/z): 404 (MN). (e") 7.4.383 2-chloro-5-fluoro-M-(1-methylindazoline-b- Similar to the preparation of 2-chloro-M4-(3,4-styrenedioxyphenyl)-5-fluoro-4-pyrimidinamine, etc.) -A-pyrimylinamine (935394) 2-chloro-5-fluoro-M-(1-methylindazolin-6-yl)-4-pyrimidinamine is obtained as a result of the reaction of h-2,A-dichloro-5-fluoropyrimidine and 6b-amino- 1-methyl-indazoline. "H NMR (0M5O-46): b 10.15 (8, IN), 8.34 (y, 1H, 2 3.5 Hz), 8.00 (5, 1H), 7.98 (arr 5, IN), 7.72 (4, 1H, 22 8.2 Hz), 7.39 (48, s

IN, I1-8.2 Hz), 3.81 (5, ZN). LC/MS: retention time: 10.45 min.; purity: 9595; MS (m/z): 278 (MN).

Zo 7: I tt tt (ge) 7.4.384 14243-chloro-4-hydroxy-5-methylphenyl)-3- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-fluoro-M4-(1-methylindazolin-b-yl)-2,4-pyrimidinediamine, M2- (3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-M4-(1-methylindazoline-6-pyrimidinediamine (2935395)yl)-2.4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M4 (1-methylindazolin-b-yl)-4-pyrimidinamine and 4-amino-2-chloro-b-methylphenol. "H NMR (0M50-46): b 9.48 (8, 1H), 9.06 (5, IN), 8.58 (c, 1H), 8.11 (y, IN, 7- 3.5 Go), 8.07 (5, 18), 7.93 (5, 1H), 7.55 (4, 1H, 7- 8.8 Hz), 7.56 (5, 1H), 7.35 (04, IN, 3-: 2.3 and 8.5 GI), 7.21 (4, IN, « 122.3 Hn), 3.87 (5, ZN), 1.99 (5, ZN).. РХ /MS: retention time: 9.13 min, purity: 95955

MS (m/z): 399 (MN). from 7.4.385 M4-(3,4-dichlorophenyl)-5-fluoro-M2-12-(2- Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2 ,4-s methoxy-4-pyrimidinediamine, M4-(3,4-dichlorophenyl)-5-fluoro-M2-12-(2-methoxy-4-h methoxycarbonylbenzyl)indazolin-6b-yl|- | methoxycarbonylbenzyl)indazolin- b-yl)|-2,4-pyrimylindiamine is obtained as a result of i-2,4-pyrimidinediamine (K935396) reaction of 2-chloro-M-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidinamine and b-amino -2-(2-methoxy-4-methoxycarbonylbenzyl)indazoline. PH/MS: retention time: 14.80 min.; purity: 9492; MS (m/3): 568 (MIG). 7.4.386 M44(3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similarly to the preparation of M4-(3,4-ethylenedioxypheny)-5-fluoro-M24(3-hydroxyphenyl)-2,4- (2-(2-methoxy-4. pyrimidinediamine, 4-(3,4-dichlorophenyl)-5 -fluoro-M2-12-(2-methoxy-4-(ee)methoxycarbonylbenzyl)indazolin-b-yl|- | methoxycarbonylbenzyl)indazolin-b-1l|-2,4-pyrimidinediamine is obtained as a result of 2.A-pyrimidinediamine ( K935398) reactions of 2-chloro-M-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and b-amino-2-(2-comethoxy-3-methoxycarbonylbenzyl)indazoline. "H NMR (0М5О0 -46); 5 9.80 (5, IN), 9.66 (5, and 1H), 8.32 (5, EN), 8.16 (4, 1, 3-- 4.4 Go), 7.90 (5, 1), 7.71 (4, 2H, 1- 3.5 Gu), 7.61 (4, 1H, 1- -y (Se) 42) ko 60 b5

82 g), 7.525, 1), 7.494, 1H, 1-82 g), 7.154, 1H, 2-85 g), 7.090, 1H, 1-85 Hn), 6.894, 1H, 1- 8.5 Hz) . purity: 9495; MS (m/z): 563 (MN). 7.4.387 ma-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5- fluoro-M2-(3-(M-11-(2-methoxy-444M-methylamino)carbonylmethyleneoxyphenial)-2,4-pyrimidinedismine, M4-(3,4- methylaminocarbonyl)benzyl|indazolin- ethylenedioxyphenyl)-5-fluoro- M2-11-|2-methoxy-4-(M-methypaminocarbonyl)bgnzy|indazolin-o-yl)-2,4-pyrimidinediamine (K935399) 6-ipu-2,4-pyrimidinediamine is obtained as a result of the reaction M4-(3 ,4-ethylenedioxyphenyl)-5-fluoro-M2-|1-(2-methoxy-4-methoxycarbonylbenzyl)indazolin-b-yl)|-2,4-pyrimidinediamine and tetrachloride. "H NMR (PM5О0-46); 5 9.15 (5, 1Н), 8.42 (4, 1Н, 7- 3.5 Hz) 8.20 (5, 1), 8.06 (4.1Н , 15 3.3 Hz), 85.05 (5, 1H), 7.50 (40, 1H, and 8.8 Gy), 7.45 (5, 1H), 7.34 (44, IN, 3 - 1.2 and 7.6

Hz), 7.28-7.26(t,2H), 7.18 (44, IN, 7- 2.3 and 8.3 Gy), 6.93 (d, 1H, 7: 7.6 Hz ), 6.77 (48, 1H, 122.3 and 8.8 Hu, 5.57 (5, 7NI)., 4.18 (5, 4H), 3.88 (5, ЗН), 2.76 (4, ZN, 7 3.5 Gy). LC/MS: retention time: 9.03 min.; purity: 9195; MS (m/z): 556 (MN). 7.4,388 43, 4-difluorofenip) -5-fluoro-M2- Similar to the preparation of M4-4(3,4-ethylenedioxyphenyl)-5-fluoro-Mm2-(3-tihydroxyphenyl)-2,4"(indazolin-b-yl)-2,4-pyrimidinediamine pyrimidinediamine . -5-fluorine of 4-pyramidinamine and 6-aminoindazoline. "H. NMR (0М50-46): 5 9.66 (5, IN), 9.56 (5, IN), 8.20 (а, 1Н, 12 4 7), 8.16-8.05 ( t. 40, 1, 215: 1.7 and 8.8 Gy). LC/MS: retention time: 10.39 min.; purity: 9495; MS (mach; 357 (MN). 7.4.389 MA-(3, 4-difluorophenyl)-5-fluoro-M2-(1- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro- M2-4(3-hydroxyphenyl)-2,4- methylindazolin-b-yl)- 2,4- pyrimidinediamine, M4-(3,4-pifluorophenyl)-5-fluoro-M2-(1-methylindazolin-b-yl)-72,4- pyrimidinediamine (K935401) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M4 (3,4-difluorophenyl)-5-fluoro-4-pyrimidinamine and 1-methyl-b-aminoindazole. 1H NMR (OM50-46): 6 10.15 (5, IN), 19.09 (5, 1H ), 8.294, 1H, I- 4.1 Gy), 8.03-7.97 (t, 1H), 7.93 (5, 1H)U, 7.88 (5, 1H), 7.65 ( 4, IN, 7-8,8

Go), 7.50-7.52 (t, 18), 7.37 (0, 1H, 1- 8.3 and 19.4 Hz), 7.21 (d, IN, 1- 8.3 Gy ), 3.84 (5, ZN).

LC/MS: retention time: 11.78 min.; purity: 9895; MS (m/z): 371 (MN). 7.4.390 Ma (3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Analogous to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-(1-methylindazolineb-yl)-2,4-pyrimidinediamine, М4-(3-chloro-4 -methoxyphenyl)-5-fluoro-M2-(I-methylindazolin-6-yl)n2,4-pyrimidinediamine (K935402) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M-(3-chloro-4-methoxyphenyl)-5- fluoro-4-pyrimidinamine and | -methyl-b-aminoindazole. "H NMR (0М50-46): δ 9.43 (5.14), 9.37 (5.18), 5148, 1Н, 7-2 3.5 Hz), 7.99 (5, 1Н), 7.83-7.81 (t, 2), 7.69-7.65 (t, KN), 7.54 (4.1H, 1-88 Hz), 7.21 (9, 1H, 1 8 ,2 tsu, 7, (8, 1H, 1 8.8 Go), 3.87 (5, ZN), 3.72 (5, ZN).

LC/MS: retention time: 10.60 min.; purity: 9400; MS (m/z: 399 (MN). s 74391 M4-(3,4-dichlorophenyl)-M2-|1-(2- Analogous to the preparation of IM4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-( 3-Hyloxyphenyl)-2,4-He)ethoxycarbonylethyl)indazolin-b-yl|-5-pyrimidinediamine, M4-(3,4-dichlorophenyl)-M2-H1-(2-ethoxycarbonylethyl)indazolin-6-yl|- 5-fluoro-2,4-pyrimidinediamine (К935403) fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M-(3,4-dichlorophenyl)-5-fluoro-4-pyrimidinamine and b-change- 14 (2-ethoxycarbonylethyl)indazoline. "IN NMR (OM50- ab): 6 9.65 (5, 1H), 9.53 (5, 18), 8.22 (y, IN, 3-- 3.5 Hz), 8.12 (6 IN, 3-2.9 Go), 8.00 (8, 1H), 7.99 (5, 1H), 7.82 (arr dy, IN, /- 2.9 and 8.8 Hzu, 7, 57 (d, 1H/1: 8.8 Gy), 7.53 (9, 1H, )- 8.8

GyX 7.28 (4, 1H, 1» 8.8 Hz), 4.34, 2, 12 6.4 Gy), 3.94 (45 2H, 1- 7.0 Hn), 2.83 (6 ZN, 4-64 (Che)

Hz" 1.04 (, ЗН, 3-7.0 Gy). PH/MS: retention time: 14.36 min.; purity: 9995; MS (m/z): 490 (МН. b 7.4.392 М4А4(3,4-dichlorophenyl)-5-fluoro-М2-41- Analogous to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2- /3-(M- - methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(3 4-dichlorophenyl)-5-methylamino)carbonylethyl|indazoline-b-fluoro-M2-11-H(m-methylamino)carbonylethyl |indazolin-6-yl)-2,4-pyrimidinediamine h--yl)-2,4-pyrimidinediamine (К935404) is obtained as a result of the reaction М4-(3,4-dichlorophenyl)-М2-2Х14(2-ethoxycarbonylethyl)indazolin -b-yl)|-5-fluoro-2,4-pyrimidinediamine and sem methylamine hydrochloride. "H NMR (0M50-46): 5 9.64 (in, 1), 9.51 (5, EN), 5.22 (0, 1H, 1- 3.5 Go), 8.13 (5, 1H,3- 2,9 Gy), 7,95 (in, NI), 7,89 (5, IN, 7,85-7,79 (t, 28), 7,58 (f, 1, 72 8 .8 Sy), 7.55 (4, so

IN, 21-88 Hz), 7.29 (6, 1, 1-: 8.8 Hz), 4.33 (6 2H, 2-64 Hz), 2.600 2H, 7 6.4 Hyd), 2, 48 (4,

ЗН,И - 3.5 Hz). PH/MS: retention time: 11.09 min.; purity; 9595; MS (m/z): 475 (M). 7.A.393 M4-(3,A-dichlorophenyl)-5-fluoro-M2-143- Similar to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-fluoro-M4-(K2-hydroxy 41,1. tihydroxypropyl )indazolineb-yl|-2,4" dimethylethyl)phenyl|-2,4-pyrimidinediamine, IM4-(3,4-dichlorophenyl)-5-fluoro-M2-Y4(3-"pyrimidinediamine (935405) hydroxypropyl)indazolin- b-ich1-2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(3,4-dichlorophenyl)-M2-11-(2-ethoxycarbonylethyl)indazolin-0-yl|-5-fluoro-2,4-pyrimidinediamine and diisobutyllithium aluminum hydride . "H NMR (0М5О0-46): 8 9.72 (in, shsh

IN), 9.59 (5, 1), 8.29 (0, 1H,3 23.5 Hz, 8.20 (, 1H, 12 2.9 Hz), 8.02 (5, 1H), 7 .96 (5, 1H), s 7.908, 1H, 5-8.8 Gy), 7.66 (y, 1H, 1: 8.8 Hz), 7.61 (4.18, 3 8.8 H ), 7.380, 1H, 1- 8.8 Gy), 4.58 (1, IN, 1- 4.7 Gy), 4.26 (vrr 1, 2H, 1 6.4 Hn), 3.36 ( рr с, 2Н, 3- 7.0 Го), 1.94 (а, 2Н, 1- h з» 6.А Hz). PH/MS: retention time: 11.84 min.; purity: 9495; MS (m/z: 448 (MN. n 7.4.394 1444(3-chloro-4-methoxyphenyl)-M2-(11-(2- Analogous to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-fluoro-M2 -(3-hydroxyphenyl)-2,4-ethoxycarbonylethyl)indazolin-b-1l|-5-pyrimylindiamine, M4-(3-chloro-4-methoxyphenyl)-M2-I-(2-ethoxycarbonylethyl)ndazolin-6-fluoro -2 4-pyrimidinediamine (5935406) ily-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M-(3-chloro-4" methoxyphenyl)-5-fluoro-4-pyrimidinamine and 5-amino - 1-(2-ethoxycarbonylethyl)i ndazoline, so IN YAM? ,5 Gy), 8.01 (5, 18), 7.87 (5, 1NU, 7.83 1H, 7-5 2.9 Gy), 7.71-7.66(t,1H), 7 .54 (9, 1H, 7: 8.8 Hz), 7.27 (8, IN, 7-88 Gy),

TlO(I, IN, I 8.6 Hz), 4.28 (OH, 1- 6.4 Hz), 3.93 (di, 2H, 7 7.0 Hz), 3.82 (5, ZNI) . ) 42) ko 60 b5

2H, 1-6.4 Gy), 1.03 (i, ЗН, 1- 7.0 Hz), РХ/MS: duration of retention; 11.77 min.; purity: 9895; MS (m/z): 486 (MN). 7.4.395 ma-(3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similarly to the preparation of M2-(3,4-ethylenedioxyphenyl)-5-fluoro-M4-14(2-hydroxy-1,1- (14(3-hydroxypropyl)indazolin-b-1l1-2,4- | dimethylethyl)phenyl) |-2,4-pyrimidine plyamine, M4-(3-chloro-a-methoxyphenyl)-5-fluoro-M2-11-(3-pyrimidinediamine (KU35407) shydroxypropyl)indisoline-b-yl|-2,4-pyrimidinediamine are obtained as a result of the reaction of M4-(3-chloro-4-methoxyphenyl)-M2-11-(2-ethoxycarbonylethyl)indazoles-b-1l)-5-fluoro-2,4-pyrimidinediamine and dimethylaluminium tetrachloride. "H NMR (0M5O0-4b); 5 9.38 (5, IN), 9.35 (5.180, 8.13 (0, 1H, 1- 3.5 Gaius), 7.95 (5, 1), 7.85 (5, 1H), 7.84 (arr 6, IN, 72 2.9 Gy), 7.70-7.65 (t, NU, 7.55 (d, IN, 3- 8.8 Hz), 7.29 (d, IN, 1- 8.8 Hz), 7.109, 1H, 7- 8.8 Gy), 4.48 (BIN, 1- 553 Go 13 (5 2H, 3-7, Г и), 3.82 (5, ЗН), 3.26 (и, 2Н, 1-7.0 Ги), 1.83 (arr d, 2Н, 1-70 Hz). LC/MS: retention time : 9.34 min,; purity: 9795; MS (m/z): 443 (Mn. 7.4,396 4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(3 ... -fluoro-M2-(indazolin-b-yl)-2,4- (935408) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M3-chloro-4-methoxyphenyl)-3-fluoro-4-pyrimidinamine and b-aminoindazoline. "H NMR (OM50-yb); 5 12.64 (5, IN), 9.27 (5, 2H), 8.08 (4, 1H, 2-2 3.5 Hz), 7.98 (5 , 1H)), 7.83 (8, 1H)), 7.80 (4, 1H, 12 2.9 Hz), 7.73 (44, 1, 1 2.9 and 8.8 Hz), 7.51 (4, 1Н, 3- 8.8 Hz), 7.250, 1НЙ, 3- 8.8 Н), 7.048, 18, 1- 8.8 Hz), 3.78 (5,

ZNU PH/MS: retention time: 9.46 min.; purity: 9295; MS (m/z): 385 (MN). 7.4.397 M443-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-(A-11-2-methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamive, M4-(3-chloro-4- methylaminocarbonyl )ethyl|indazolin-6-methoxyphenyl)-5-fluoro-M2-1-|2(U-methylaminocarbonyl)ethyl|innazolin-b-yl)-2,4»yl)|-2,4-pyrimidinediamine (9354093 pyrimidinediamine obtained as a result of the reaction of M4-(3-chloro-4-methoxyphenyl)-M2-|1-(2-ethoxycarbonylethyl)indazolin-b-yl-5-fluoro-2,4-pyrimidinediamine and hydrochloride.

NMR (0M50-46): 6 9.39 (8, 1). 9.35 (5, IN), 8.144, 1Н, )- 3.5 Gah), 7.96 (5, ENN), 7.85 (d,

IN, I- 1.2 Hn), 7.83 (6, IA, 1-23 Gy), 7.79(a; 1H, 7-4.7 Hz, 7.68 (49, IN, 7- 2.3 and 8.8 Gy), 7.54 (4, IN, 2: 8.8 Ha), 4.28 (B, 2H, P 7.0 Gy), 3.82 (5, ZNU, 3.30 ( 9, ZN, 7- 4.7 Go), 2.56 (, 2Н, 1- 7.0 Hz). LC/MS: retention time: 8.98 min.; purity: 9375; MS (m/z) : 471 (МН. 7.4.398 5-fluoro-Ма4-(4-fluoro-3-methoxyphenyl)-5- Similar to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-(3-hydroxyphenyl) - 2,4.fluoro-M2-(1-methylindazolin-5-11)-2,4-pyrimidinediamine, 5-fluoro-M4-(4-fluoro-3-methoxyphenyl)-5-fluoro-M2-(1- methylindazolin-5-yl)" pyrimidinedigmine (K935410) 2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M-(4-fluoro-3-methoxyphenyl)-4-pyrimidinamine and I-methyl-5-aminoindazoline. "H YAM? (0M5O-46): 5 9.32 (5, 1H), 9.18 (5, IN), 812-811 (t, IN), 8.09 (4, 1H, 72 3.5 Guide), 7.79 (arr d, 1H,, U 1.8

Gy), 7.51-7.47 (t, ZNU, 7.37-7.32 (t, KNU, 7.13 (44, 1H, 7-5 8.8 and 11.1 g), 3.98 ( c, ZA), 3.68 (5, ZN). PH/MS: retention time: 9.18 min.; purity: 9895; MS (m/z): 383 (Mn. c 7.4.399 Ma-(4 -chloro-3-fluorophenyl)-5-fluoro-M2-(1- | Similar to the preparation of M4A-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- o methylindazolin-5 -1l)-2,4- pyrimidinediamine, M4-(4-chloro-3-fluorophenyl)-5-fluoro-IIM2-(1-methylindazolin-5-yl)-24-pyrimidinediamine (K935411) pyrimidinediamine is obtained as a result of reaction 2 -chloro-M-(4-chloro-3-fluorophenyl)-5-fluoro-4-pyrimidinamine and I-methyl-5-aminoindazoline. "H NMR (0M50-96): δ 9.60 (5, 1H), 9.31 (5,

IN, 8.16 (4, 1H, 2- 3.5 Hz, 813-811 (t, 1), 8.08 (5, 1H), 7.86 (5, 11), 7.60-7, 54 (t, 1), 7.51-7.42 (t, ZN), 3.99 (5, ZN). RH/MS: retention time: 9.87 min.; purity: 10095; "se

MS (ml): 387 (MH). 7.4.400 ma(3,4-dimethoxyphenyl)-5-fluoro-M2-(1- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- F methylindazolin-5-1l)-2,4-pyrimidinediamine, M4-(3,4-dimethoxyphenyl)-5-fluoro-M2-(1-methylindazolin-5-yl)-2,4-pyrimidinediamine (KU35412) pyrimidinediamine is obtained in as a result of the reaction of 2-chloro-M-(3, 4-dimethoxyphenyl)-5-fluoro 4-pyrimidinamine and I-methyl-5-aminoindazoline. "H NMR (0M5O0-46): 5 10.21 (5, 18), 1012 chi (v, 13), 5.18 (4, 1H, 32 5.3 Gy), 7.96 (5, 1H) , 7.85 (5, IN), 7.57 (4, IN, 1- 8.8 Hn, 7.36 (4, 1H, 1- 8.8 Ha), 7.23-7.17 (t , 2NI), 6.89 (d, IN, 7-2 8.8 Hz), 4.00 (5, ZN), 3.75 (5, ZN), 3.57 (in, ZI). Ha

LC/MS: retention time: 7.80 min.; purity: 9995; MS (m/z): 395 (MN). 7-4.401 M2-3-chloro-4-methoxy-5-methylphenyl)-5- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-s fluoro-M4-(indazolin-b-yl)-2,4-pyrimidinediamine, M2-( 3-chloro-4-methoxy-5-methylphenyl)-5-fluoro-M4-(indazolin-6-1l)-2,4-pyrimidinediamine (K93413) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M- (indazolin-b-yl)-4-pyrimidinamine and 3-chloro-4-methoxy-5-methylaniline. /"H NMR (0M5O0-46); 5 12.88 (5, 1), 9.49 (5, 1H), 9.25 (5, 1H), 8.13 (0, IA, 1-: 3 .5 Gu, 7.98 (5, 1H), 7.79 (in, 1H), 7.69 (4, IN, 1- 8.8

Hz), 7.63 (8, IN, 12 2.3 Hz), 7.45 (49, 1H, - 1.9 and 8.8 Hz), 7.42 (y, 1H, 1 2.3 Hz ), 3.63 (in,

ZN), 201 (5, ZN). LC/MS: retention time: 10.87 min.; purity: 9595; MS (m/z): 399 « (MN). 406 7.4.402 a-(4-chloro-3-fluorophenyl)-5-fluoro-IM2- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- shsh "indazolin-b-yl)-2,4-pyrimidinediamine of pyrimidinediamine, M4-(4-chloro-3-fluorophenyl)-5-fluoro-M2-(indazolin-b-yl)-2,4-s (Кк935414) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M-(4-chloro-3-fluorophenyl)-5-fluoro 4-pyrimidinamine and 6-aminoindazoline. IN NMR (PM5O-46): 5 9.71 (5, 1H), 9.55 (5, 18), "» 8.20 (i, 1H,, 12 2.3 Hz), 8.22 (i , IN, 2- 3.5 Hz), 8.16 (arr 4, IN, 7: 2.3 Hz), 8.07 (5, 1H), 7.91 (5, IN), 7.65 (4 , 1H, 12 8.8 Gy), 7.594, 1H, 3-2 8.8 Hz), 7.47 0, 1H, 7: 8.8 Gy), 7.25 (ab, IN,

C - 1.8 and 8.8 Hz). PH/MS: retention time: 9.02 min.; purity; 10075; MS (m/z); 373 (M. 7.4.403 Ma-(4-chloro-3-fluorophenyl)-5-fluoro-M2- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2 ,4-"indazolin-z-yl)-2,4-pyrimidinediamine pyrimidinediamine, M4-(4-chloro-3-fluorophenyl)-5-fluoro-M2-(indazolin-5-yl)-2,4- (22 ) 4IK935415) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M(4-chloro-3-fluorophenyl)-5-fluoro 4-pyrimidinamine and 5-aminoindazoline, "H NMR (0OM50-46): 6 10.36 (5, 1H), 10.09 (5, 1H),

Kz 8.27 (4, EN, 1- 4.7 Gy), 7.97 (5, IN), 7.95 (in, IN), 7.90 (5, NN), 7.52 (9, IN, 7" 8.8 Go), 7.50 (y, -y (Se) 42) ko 60 b5

IN, 128.8 Gy), 7.46 (0, EN, 1: 8.8 Gy), 7.39 (409, IN, 7-5 1.8 and 8.58 Hz). RH/MS; retention time: 9.87 min.; purity: 10095; MS (m/z): 387 (MN). 7-4.404 5-fluoro-Ma-(4-fluoro-3-methoxyphenyl)-M2- | Similarly to the preparation of M4A-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-(indazolin-b-yl)-2,4-pyrimidinediamine pyrimidineliamine, 5-fluoro-M4-( 4-fluoro-3-methoxyphenyl)-M2-(indazolin-6b-yl)-2,4- (8935416) pyrnmidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M-(4-fluoro-3-methoxyphenyl) -4-pyrimidinamine and b-aminoindazoline. "H NMR (0M50-46): 5 12.70 (5, 1H), 9.35 (5, IN), 9.32 (5, 1H), 5144, IN, 2-4.1 Hz), 8 .07 (5, IN), 7.88 (5, 10), 7.54 (44, 1H, 13.5 and 8.8 Gy), 7.50-7.46 (t, 2H), 7, 26 (04, 1H, 31.2 and 8.2 Gy), 7.11 (04, 1H, 1-8.8 and 11.8 Gy), 3.72 xx, ЗН). РХ/MS: retention time: 9 ,34 min.; purity: 9300; MS (m/z): 369 (MH). 7.4.405 5-fluoro-Ma-(4-fluoro-3-methoxyphenyl)-M2- | Similar to the preparation of M4-(3, 4-ethylenedioxyphecyl)-5-fluoro-142-(3-hydroxyphenyl)-2,4-(indazopin-5-yl)-2,4-pyrimidinedismine pyrimidinediamine, 5-fluoro-M4-(4-fluoro-3-methoxyphenyl )-M2-(indazolin-5-yl)-2,4- (8935417) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-YH-(4-fluoro-3-methoxyphenyl)-4-pyrimidinamine and 5- aminoindazoline. /"H NMR (OM5O-4b): δ 12.84 (5, 1H), 9.33 (5, IN), 9.16 (5, 1H), 8.094, 1H, 1- 3.5 Gy ), 7.83 (z, 1H), 7.49 (00, 1H, 7- 2.3 and 8.3

Gi), 7.43 (40, 1H, 3-23 and 8.3 Ga), 7.37 (4, 1H, 3-- 8.8 Go), 7.35-7.30 (t, 28) , 7.11 (IF H, 1-88 and 11.1 Hz), 3.67 (5, ZN). LC/MS: retention time: 85.09 min.; purity: 9790; MS (m/z: 369 (MI). 7.4.406 M2-(3-chloro-4-methoxy-5-methylphenyl)-5- | Similar to the preparation of M4-(3 4-ethylenedioxyphenyl)-5-fluoro-M2- (3-hydroxyphesnyl)-2,4-fluoro-Ma-(4H-imidazo|2,1-c1-pyrimidinediamine, M2-(3-chloro-4-methoxy-5-methylphenyl)-5-fluoro-M4-14H -imidazo|2,1-c1- benzyl and ,Doxazin-8-yl)-2,4-benzP1.4oxazin-b-yl)-2,4-pyrimidinediamine is obtained as a result of the resection of 2-chloro-5-pyrimidinediamine (K9354183 fluoro-M-(4H-imidazo 2,1-c|-benz/1,oxazine-8-1l)-4-pyrimidinamine and 3-chloro-4-methoxy-5-methypaniline. "H NMR (0M5O-96) ; 6 9.48 (in, 1H), 9.27 (in, IN), 8.11 (9, IN, 12 3.5 Gy), 7.994, 1H, 3-2.3 С), 7.71 (5 , 1H), 7.64 (8, 1H, 12.3 Hn), 7.35 (44, 1H, 7- 2.3 and 8.8 Go), 7.31 (8, IN, 2: 2, 3 Gy), 7.13 (4, 2HB, 17 8.8 Gy), 5.26 (5, 7H), 3.58 (5, ЗН), 2.01 (8, ЗН).

LC/MS: retention time: 10.68 min.; purity: 9590; MS (m/z): 453 (MN). 7.4.407 M2-(3-chloro-4-methoxy-5-methylphenyl)-5- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-fluoro-Ma-(1-methylindazolin-b-1l)-2,4-pyrimidinediamine, M2- (3-chloro-4-methoxy-5-methylphenyl)-5-fluoro-M4-(1-methylindazoline-b-pyrimidinediamine (К935419) yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro -M-(1-methylindazolin-b-yl)-4-pyrimidinamine and 3-chloro-4-methoxy-5-methylaniline. /"H NMR (OM50-a6): 510.17 (5, 1H)), 9.87 (5, 1H), 8.25 (0, 1H, /- 3.7 Hz), 7.99 (5 , 1H), 7.96 (5, 1H),

And IN, 8.2 g), 7.58 (1, 12 2.3 Gy), 7.37 -7.33 (t, 1H)), 7.26 (8, IN), 3.89 (5 , ZN), 3.64 (5, ZN), 2.02 (in, ZN); VH/MS: retention time: 12.15 min.; purity: 9895; MS (m/z): 413 (Mn. ch 7.4.408 1M2-(3,5-dimethoxyphenyl)-5 rtor-M441- Analogously to the preparation of 14Ch4-(3,4-ethylenelioxyphenyl)-5-fluoro-M2-(3 -hydroxyphenyl)-2,4-He) methylindazolin-b-yl)-2,4-pyrimidinediamine, M2-43,5-dimethoxyphenyl)-5-fluoro-4-(1-methylindazolin-b-yl)-2, 45 pyrimidinediamine (K935420) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M-(1-methylindazolin-b-i1)-4-pyrimidinamine and 3,5-dimethoxyaniline. "H NMR (2M50-46): 5 10.67 (5, 1H), 10.44 (5,

IN), 8.36 (d, 1H, 12 4.9 Hz), 8.01 (5, 2H), 7.72 (4, 1H, 1- 8.8 P n), 7.32 (4, IN, /- 8.8 Gy), 6.70 (5, 2H), 6.21 (5, 1H)), 3.87 (in, ЗН), 3.52 (5, 6H). LC/MS: retention time: 10.75 min.; purity: 10095; MS (m/z): 395 (Mn. (Che) 7.4.409 2-(4-chloro-2,5-dimethoxyphenyl)»5-fluoro- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5- fluoro-42-(3-hydroxyphenyl)-2,4- 144-(1-methylindazolin-b-yl)-2,4-pyrimidinediamine, M2-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro- M4-(1-methylindazolin-b-yl)-2,4- (e") pyrimidinediamine (K935421) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M-(i-methylindazolin-6-yl)-4 -pyrimidinamine and 4-chloro-2,5-dimethoxyaniline. "H NMR (0M5O-46): δ 9.56 (5, 2H), 8.13 "-- (4,1H, 1-45 Hn), 8.055 , 1H), 7.92 (5, 18), 7.81 (4, 1H,, I 5.0 Hz), 7.62 (4, 1H, 7: 8.8 Hz), 7.31 (84 , 1Н, 3- 5.0 and 8.8 Hz), 7.06 (5, IN), 3.88 (5, ЗН), 3.78 (5, ЗН), 3.30 (5, ЗН) . LC/MS: retention time: 12.81 min; purity: 10095; MS (m/3): 429 (Mn. se 74510 1M2-(3,5-dimethoxyphenyl)-5-fluoro-M4- Analogously to the preparation of 144- (3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-

C5 (indazolin-b-yl)-2,4-pyrimidinediamine pyrimidinediamine, M2-(3,5-dimethoxyphenyl)-5-fluoro-M4-(indazolin-b-yl)-2,4-(se) (8935423) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M-(indazolin-6b-yl)-4-pyrimidinamine and 3,5-dimethoxyaniline. "H NMR (0OM50-a6): 5 10.52. (5.18), 10.26 (5, 1H), 804.1 H, I: 5.3 C), 8.035, 1), 7.57 (8, 18), 7.69 (4, 1H, 75: 8.85 10), 7.42-7.37 (t, 1), 6.689, 2H, I: 2.3 Hz), 6.150, 1H , 25: 2.3 Hz), 3.49 (5.6N). LC/MS: retention time: 9.23 min.; purity: 10095; MS (m/z): 381 (MN), « 14.1 M2 -(2,2-dimethyl-3-oxo-4H-) Analogous to the preparation of 134-(3,4-styrenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-benz/1,oxazine-b- yl)-5-fluoro-M4-01-pyrimidinediamine, M2-(2,2-dimethyl-3-oxo-4H-benz and 4|oxazin-b-yl)-5-fluoro-1M4-(1-methylindazoline -6-yl)-2,4-methylindazolin-b-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro- with pyrimidinedimine (2935424) M-(1-methylindazolin-b-yl) -4-pyrimidinamic and b-amine-7,2-limethyl-3-oxo-H4H.benzi1Aloxazine. "H NMR (OM50-46): 6 10.65 (5, 1H), 8.200, IN, 3-4, 7 Hn), 8.06 (5, n » 1H), 7.97 (5, 1H), 7.67 (60, IN, I: 8.5 Hz), 7.43-7.38 (t, 1H), 7.13 (4, 1H, 72 8.8 Hz), 7.00 (5, and 189), 6.78 (0, IN, 7- 8.8 Hz), 3.91 (5, ЗН) , 1.36 (5, 6H). PH/MS: retention time: 9.20 min.; purity: 10095; MS (m/z): 434 (MN). 74412 ma-(3-chloro-4-fluorophenyl)-5-fluoro-M2-(1- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-7,4 - methylindazolin-b-yl)-2,4-pyrimidinediamine, M4-(3-chloro-4-fluorophenyl3-5-fluoro-M2-(1-methylindazolin-b-yl)-2,4-so pyrimidinediamine (K935425) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M-(3-chloro-4-fluoropheny)-5-fluoro-4-pyrimidinamine and 1-methyl-b-aminesindazoline. "H NMR (OM5O-46): 8 9.57 (5, 1H), 9.51 (5, 1), 8.21 (4, IN, 1: 3.5 Hn), 8.06 (4, IN, 1-1 Gy), 7.98 (5 . - 9.0 and 8.8 Hz), 7.24 (4, 1H, 2-14, 90 -th (Se) 42) ko 60 b5 and 8.8 Hz), 3.79 (5, ЗН). LC/MS: retention time: 12.34 min., purity: 9795, MS (m/z): 387 (Mn. 7.A4.413 Ma-(3-chloro-4-fluorophenyl)-5-fluoro-M2 -(1- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-h2-(3-hydroxyphenyl)-2,4- methylindazalin-5-yl)-2,4-pyrimidinediamine, M4-(3 -chloro-4-fluorophenyl)-5-fluoro-M2-(1-methylindazolin-5-yl)-2,4- pyrimide indiamine (2935426) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M-(3-chloro-4-fluorophenyl)-5-fluoro-4-pyrimidinamine and 1-methyl-5-aminoindazoline. "H NMR (OM5O-46): 6 9.47 (5, 1H), 9.25 (5,

IN), 8.13 (9, IN, 7/2 3.5 Hz), 8.01-7.98 (t, 28), 7.84 (5.1), 7.77-7.74 (t, 1Н) , 7.50 (8, 28), 7.34 (arry IN, 7: 9.0 Gi), 3.99 (5, ZN). LC/MS: retention time: 10.80 min.; purity: 9895; MS (m/z): 386 (Mn. 7.4.414 Ma4-43-chloro-4-fluorophenyl)-5-fluoro-M2" Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-( 3-hydroxyphenyl)-2,4-(indazolin-6-yl)-2,4-pyrimidinediamine pyrimidinediamine, M4-(3-chloro-4-fluorophenyl)-5-fluoro-M2-(indazolin-b-yl)- 2,4- (К935427) pyrimidinediamine is restrained as a result of the reaction of 2-chloro-M-(3-chloro-4-fluorophenyl)-5-fluoro-4-pyrimidinamine and 6-aminoindazoline. "H NMR (0M50-46): 5 12.72. (5, 1H), 9.52 (z, IN), 9.43 (5, 1H), 8.194, 18, 2- 3.5 Gy), 8.08-8.04 (t, 2H), 7.89-7.83 (t, 2H), 7.58 (a, 1H, 1- 8.8

Gi), 7.35 1H, 259.0 Hz), 7.26 (4, 1H, 75 8.8 Hz). RHLIS: the duration of the gathering: 10.26 min.; purity: 9495; MS (m/z): 373 (MN). 7.45.415 M44(3-chloro-4-fluorophenyl)-5-fluoro-M2- Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-

Sinlazolin-5-yl)-2,4-pyrimidinediamine pyrimidinediamine, M4-(3-chloro-4-fluorophenyl)-5-fluoro-M2-(indazolin-5-yl)-2,4- (8935428) pyrimidinediamine is obtained in as a result of the reaction of 2-fluoro-M-(3-chloro-4-fluorophenyl)-5-fluoro-4-pyrimidinamine and 5-aminoindazoline. Н ЯМе (рМ50-а45): 6 10.14 (5, 1), 9.92(5.1Н), 8.24 (4, IN, 1- 4.9 Gy), 7.97-7, 89 (t, ZN), 7.69-7.65 (t, IN), 7.49 (y, IN, 3-8.8 Gy), 7.40 (a,

IN, 12 10.8 Hz), 7.34 (y, IN, 72 10.8 Gy). PH/MS: retention time: 9.42 min.; purity: 9625; MS (m/z: 373 (MN). 74416 Salt of benzylsulfonic acid M4-M442,2-dimethia-3-oxo-4H-benzi 1,4 |oxaznn-b-1l)-5-fluoro-M4-(indazoline- β-yl)-2,4-(2,2-Dimethyl-3-oxo-YAN-pyrimidinediamine (1.5 g, 3.57 mmol) in MEOH (20 ml) is cooled to 0 °C. To this mixture, benzene 1,4 |oxazin-b-zl)-5-fluoro-M4- benzalsulfonic acid (0.594 g, 3.75 mmol, (indazolin-6-yl)-2,4-pyrimidinediamine 9895) is added dropwise over 5 min. , dissolved in SNISM (20 ml). The resulting pure solution is stirred for 15 (K935429) minutes at the same temperature, and left for 60 minutes to warm to room temperature. The pure solution precipitates. The reaction mixture is concentrated, dissolved in MeOH ( 4 ml) and grind to a powder with EVUDAS:n-texane. The resulting solid is filtered and dried under high vacuum to form the salt of benzenesulfonic acid M4-(2,2-dimethyl-3-oxo-N.benzi 1,4|oxazine -b-yl)-5-fluoro-M4-(indazolin-b-yl)-2,4-pyrimidinediamine. "H NMR (OM50-46): δ 10.70 (in, i1H), 10.34 (5 ,19 ), 9.99 (5, 1), 8.21 (4, 1H,, 7» 5.3 Gy), 8.00 (y, 1, 1-.1.8 Hz), 7.67 (a , 2H, A: 8.5 Hz), 7.60-7.57 (t, 2H), 7.34-7.28 (t, 4H), 7.19 (44, 1H, 7- 8.8 and 1 ,8 Gy), 7.10 (4, 1H, 22 2.3 hours, 6.87 (4, s - 1H, 72: 8.0 Hz), 1.36 (5, 6H). retention: 8.39 min.; purity: 10095; MS Ge) nn 7.4417 Salt of p-toluenesulfonic acid M4-(2,2- Analogously to the preparation of the salt of benzenesulfonic acid M4-(2,2-dimethyl-3-oxo-4H-dimethyl-3-oxo-4H-benz( 1, oxazine- 6- Benzy 1,4-yuxazin-6-yl)-5-fluoro-M4-(indazolin-b-yl)-2,4-pyrimidinediamine salt p-yl)-5-fluoro-M4-(indazolin-b- 1l)-2,4-toluenesulfonic acid M4-(2,2-dimethyl-3-oxo-4H-benzyl)-5-fluoro-4-pyrimidinediamine (KU35430) (indazolin-6-yl )-2,4-pyrimidinediamine is obtained as a result of the reaction M4-(2,2-dimethyl-3-se oxo-4H-benz|1 4 oxazin-b-yl)-3-fluoro-IIM4-(indazolin-b-yl )-2,4-pyrimidinediamine and p-toluenesulfonic acid monohydrate. /"H NMR (PMI5O-45): 5 19.70 (5, 18), 10.22 (5, IN), 9.88 (5, 1NU, 8.19 (0, 1H, 1-5.3 Hyd), 7.999, 1H, 1-09 Hz), 7.72 (in, 1), 7.64 (a, 1H, 1-5 8.5 ( at)

TG), 7.46 (0, ZN, 1: 80 Gu, 7.34 (ad, IN, Ya- 2.3 and 8.5 Km), 7.19 (ad, 1, 7-2.3 and 8.5 Hz), 7.125, 1NU, 7.19 (y, 2Н, 7: 8.0 Gy), 6.87 (4, IN, 3- 8.5 Hz), 2.27 (5, ZNU, 1.36 (5, 6EU). h-:

PH/MS: retention time: 8.39 min.; purity: 10095; MC (ma): 420 (MN). 7.АА18 М44(2,2-dimethyl-3-oxo-4Н- Analogously to the preparation of М4-(3,4-ethylenedioxyphenyl)-5-fluoro-М2-(3-hydroxyphenyl)-2,4-sem benz(1, 4) oxazin-6-yl)-142-(1-2-pyrimilindiamine, M4-(2,2-dimethyl-3-oxo-4H.-benzi 1,4 |oxazin-6-1l1)-M2-|1 -(2-ethoxycarbonylethyl)indazolin-5-yl-5-ethoxycarbonylethyl)indazolin-5-yl-5-fluoro-2,4-pyrimidinediamine is obtained as a result of the reaction with fluoro-2,4-pyrimidinediamine (K935431) of 2-chloro- M-(2,2-dimethyl-3-ocoo-4H-benzyl|1,4|oxazin-6-yl)-5-fluoro-4-pyrimidinamine and 5-amino-1-(2-ethoxycarbonylethyl)indazoline. "H NMR (PM5O-46): 5 10.79 (5, 18), 10.48 (5, 1), 10.36 (8, IN), 8.254, 1H, 1:4.9 HH), 7 .91 (5, 181), 7.87 (5, IN), 7.63 (d, 1H, 7- 8.8

Gi), 7.38 (44, 1H, 1- 1.7 and 8.8 Hn), 7.21 (a, 1H,, 1- 8.8 Go), 7.19 (5, 18), 6 .89 (4, EN, 1- 8.8 Gy), 4.58 (1, 2H, 12 6.4 Gy), 3.97 (di, 2H, Te 7.0 Hz), 2.89 (and , 2H, 42: 6.4 i), 1.36 (5, 6H), 1.06 (B ZNO I- 7.0 Go). RHUMS: retention time: 9.52 min.; purity: 10095; MS (m/z): 520 " (Mn. 7. AAYU MA-(2,2-limethyl-3-oxo-41-) Analogously to the preparation of M2-(3,4-styrenedioxyphenyl)-5-furo-M4-|4 (2-hydroxy-1,1- benzene 1,4-ioxazin-b-yl)-5-fluoro-M2-(1-(3-| limemethylethyl)phenylI-2,4-pyrimidinediamine, carry out the reaction between M4-( 22,2-dimethyl-3-oxo-s tihydroxypropyl)indazolin-5-yl|-2,4-4H-benz PP.oxazin-b-yl)-Х2-11-(2-ethoxycarbonylethyl)indazolin-5-yl |-5-fluoro-72,4-pyrimidinediamine (K935437) with pyrimidinediamine and the action of bobutyllithium aluminum hydride. As a result of the usual treatment of x with" followed by purification by the method of column chromatography on silica gel with 295 "MeonEOAc, M4A-(2,2-dimethyl-3-oxo) is obtained -4H-Benzy 1,4|oxazin-6-yl)-5-fluoro-M2-1-(3-tihydroxypropyl)i ndazoline-5-1l|-2,4-pyrimilindismine in the form of a white solid,

LC/MS: retention time: 7.75 min.; purity: 9530; MS (m/z): 478 (MN.

TAA Ma-(2,2-dimethyl-3-oxo-4H- Similar to the preparation of M4-(3,4-styrenedioxyphenyl-5-fluoro-M2-H3-(L-(ee)benz(1,A|oxazine-b -yl)-5-fluoro-M2-41-methylamino)carbonylmethyleneoxyphenyl-2,4-pyrimidinediamine, M4-(2,2-dimethyl-3-oxo- (A 4H-benzi 1,oxazin-b-yl)-5 -fluoro-M2-41-H2(M-methylaminocarbonyl)ethyleneindazolin-5-1l)-methylaminocarbonyl)styl|indazolin-5-2,4-pyrimidinediamine is obtained as a result of the reaction M4-(2,2-dimethyl-3-oxo- 4H.io)yl|-2,4-pyrimidinedismine (2935433) benzyl E,YAPoxazin-6-15)-M2-|1-(2-ecoxycarbonylethyl)indazoline-5-gl|-5-fluoro-2,4- -y (Ce) 42) ko 60 b5 of pyrimidinediamine and methylamine hydrochloride. "YAN NMR (PM5O-46): 5 10.64 (5, 18), 9.32. (in, IN), 9.09 (in, IN), 8.09 (5, 1H)), 8.054, 1H, I-e 3.8 Gu), 7.82 (46, 1H, 1-4.4 Go), 7.78 (5, IN), 7.45 (arr 4, 2H, 1- 8.4 Hz), 7.32-7.27 (t, 1NU, 7.21 (5, 19), 6.89 (4, IN, 12 8.8 Hz), 4.50 С, 2Н. 1-70 Hz ), 2.62 (y, 2H, 2-7.0 Gy), 2.50 (9, ЗН, 1-44 Hz), 1.40 (5.68). LC/MS: retention time: 7, 45 min.; purity: 97; MS (m/z): 505 (MH). 7.4 M4A-(2,2-dimethyl-3-oxo-4H-) Similarly to the preparation of IM4-(1,4-ethylenedioxyphenyl)-5- fluoro-1M2-(3-hydroxyphenyl)-7,4-benz|1,4)oxazin-b-yl)-M2-11-(2-pyrimidinediamine, Ma-(2,2-dimethyl-3-oxo-4H) -benzi 1,4|oxyzin-6-yl)-h2-114(2- ethoxycarbonylethyl)inlazoline-b-yl-5-ethoxycarbonidethyl)indazolin-b-yl)-5-fluoro-2,4-pyrimidinediamine is obtained as a result fluoro-2,4-pyrimidinediamine (K935434) reactions of 2-chloro-M-(2,2-dimethyl-3-oxo-4H-benz(1,4 oxazin-b-yl)-5-fluoro-4-pyrimidinamine and b-amino-1-(2-ethoxycarbonylethyl)indazoline. "H NMR (0M50-46): 5 10.73 (5, 180, 1 (rg5, 1), 8.24 (0, 1H, 124.7 Hz ), 7.94 (5, 18), 7.85 (5 ) . .38 (5, 6EU), 1.03 (5, ZN). LC/MS: retention time: 10.64 min; purity: 9695;

MS (mizu: 520 (MN. 7.4.422 M4-(2,2-dimethyl-3-oxo-4H-) Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(34M- benz(1 ,4)oxazin-b-yl)-5-fluoro-M2-11-(2-/methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(2,2-dimethyl-3-oxo- (M-methylaminocarbonyl )ethyl|indazolin-|4H-benz|1,oxazin-b»yl)-5-fluoro-IM2-41-(4(M-methylaminocarbonyl)ethyl|indazolin-b-yl|-6-ip;-2, 4-pyrimidinediamine (K935435) 2,4-pyrimidinediamine is obtained as a result of the reaction of M4-(2,2-dimethyl-3-oxo-4H-benzi 1.4|oxazine-b-1l)-M2-(1-(2-stoxycarbonylethyl) of indazoline-b-1l1-5-fluoro-2,4-pyrimidinediamine and MeeMH.HCl. "H NMR (0M50-4x6): δ 10.61 (5, IN), 9.41 (5, 1H), 9, 29 (5, 1H), 8.130, 1H, 7-2 3.8 Hz), 7.86 (v, IN), 7.81 (Fi, IN, 1-4.7 Gy), 7.528, IN, 1 - 8.8 Hz), 7.40-7.30 (t, 2H), 7.27-7.25 (vrr t, 13), 6.86 (a, IN, 1- 8.5 110), 4.33 (1, 7, 1- 6.8 Hz), 2.49 (4, ЗН, 1- 3.8 Hz), 1.39 (5, 6Н). РХ/MS: duration of retention: 8, 32 min.; purity: 925; MS (m/z: 505 (MN). 74423 MA-(2,2-dimethyl-3-oxo-4H). Similarly prepared of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-benz 1,4 |oxazin-b-yl)-M2-D1- pyrimidinediamine, M4-(2, 2-Dimethyl-3-oxo-4H-benz (i,oxazin-6-yl)-M2-11-(methoxycarbonyl)methyl-indazolin-5-yl|-.- g (methoxycarbonyl)methyl-indazolin-5-yl |-5-fgor-2,4-pyrimidinediamine is obtained in 5-fgor-2,4-pyrimidinediamine (К935436) as a result of the reaction of 2-kchloro-M-(2,2-dimethyl-3-oxo-4H-benz 1,4 |oxazin-b-yl)-5-fluoro-4-pyrimidinamine and 5-amino-1-(methoxycarbonyl)methyl-indazoline. "H NMR (0M5O0-46): b 10.79 (in, IN), 10.40 (5, 1H), 10.27 (5, 1H)U, 8.23 (4, 1H, 1-5, 0 Hyd), 7.95 (5, 18), 7.92 (5, IN), 7.59 (0, 1H, 22 8.8 Gy), 7.38 (40, EN, 7- 1.7 and 8.8 Hyd), 7.23 (ad, 1, 7/2 1.7 and 8.8 Hz), 7.19 (5,

IN), 6.894, 1Н, А- 8.8 Gy), 5.36 (5, 2НИ), 3.56 (5, ЗН)), 1.36 (5, 6Н). LC/MS: retention time: 8.58 min.; purity: 9595; MS (m/z): 492 (MN). 7.4.A24 M4402,2-dimethyl-3-oxo-4H. Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-13(M» benzyl 1,oxazine-b-1l)-5-fluoro-M2-11-0U- | methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(2,2-dimethyl-3-oxosem methylaminocarbonyl)methylindazolin-5-4H-benz| 1, Aoxazin-6-1l3-5-fluoro-M2-| and (M-methylaminocarboyl)methylindazolin-5-yl)-2,4-He)yl)-2,4-pyrimidinediamine (K935437) pyrimidinediamine is obtained as a result of the reaction MA-4(2,2-dimethyl-3-oxo-4H ».benzi 1,4 |oxazin-6-1l)-M2-|1«(methoxycarbonyl)methyl-indazoline-5-1l1-5-fluoro-2,4-pyrimidinediamine and methylamine hydrochloride. 'H YAM (OMm5O-ab): 5 10.64 (5, 1), 9.29 (5, IN), 9.07 (5, 1H), 8.12 (5, 1H), 8.06 (4, 1H, 7: 3.8 Hn), 7.98 (db, 1H, 724.7 Hyd), 7.80 (in, 18), 7.56 (ai, IN, 5 2.3 and 8.8 Hz ), 7.41 (a, 1H, 1: 8.8 Gy), 7.31 (ai, EN, 1-23 and 8.8 Gy), 7.22 (arr 5, IN), 6.89 ( 4, IN, 3-2 8.8 Gy), 4.96 (5, 2H)), 2.59 (9, ZN, 2-:4.7 Gy), 1.49 (5, 6H). РЧ/МС: (Че) with duration of retention: 7.44 min.; purity: 10095; MS (m/z): 491 (MY). 7.4.425 Ш42-(2,2-dimethyl-3-oxo-4Н- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- (e") 1. Moxazki-6-1l)-5-fluoro-M4-pyrimidinediamine, M2-(2,2-dimethyl-3-oxo-4H-benz| 1, Tsoxazin-b-yl)-5-fluoro-Ma - "(Indazolin-5-yl)-2,4-pyrimidinedismine (Endazolin-5-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M- (K9354358) (indazolin-5- yl)-4-pyrimidivamine and b-amine-7,2-dimethyl-4H.-benz(1,)oxazin-3-one. "I h-

YAME (OM5O-46): 5 12.97 (5, 1H), 10.55 (5, 1H), 9.39 (in, 18), 9.04 (5, IN), 8.19 (5, IN), 8.02 (y, 1H, 223.8 Gy), 7.945, 1), 7.594y, 1H, 12:2.0 and 8.8 Hz), 7.45 (y, 1H, 1-91 Hz), 7.17 ha, se 1H, 1-20 Hz), 7.14 (5, 1H)), 5.72 (d, IN, 3- 9.1 Gu, 1.35 (z, 6H)U. LC/MS: retention time: 7.46 min.; purity: 9395; MS (m/z): 4220 (MAU. c 7.4.426 M2-(2,2-dimethyl-3-oxo-4H-) Similar to the preparation of IM4 -(3,4-ethypendioxyphenyl)-5-fluoro-M2-(3-hydroxyphenia)-2,4- benzyl,oxazin-6-yl)-5-fluoro-M4A41-pyrimidinediamine, 2-chloro-5-fluoro -YH-(1-methylindazolin-b-yl)-4-pyrimidinamine is restrained in methylindazolin-5-yl1)-2,4- as a result of the reaction of b-amine-2,2-dimethyl-4H-benz(1,4)oxazine -3-to form M2-(2,2-pyrimidinediamine (H935439) dimethyl-3-oxo-4H-benz|1,4|oxazin-b-yl)-5-fluoro-M4-(1-methylinazolin-5 -yl)-2,4-pyrimilindiamine, "H NMR (IM5O-46): 210.67 (5, 1), 10.41 (5, 1NH, 10.09 (5, 1H), 8.22 (d , « 1H, 1-4.9 Hz), 8.05 (5, 1H)), 7.93 (5, 11), 7.51 (d, 2H, I- 8.8 Hn), 7.05 (49, 1H, 55 2.3 and 8.5

Hn), 9.95 (5, 1H), 6.81 (y, 1, 3-8.5 Hz), 4.01 (5, ЗН), 1.34 (5.6). LC/MS: retention time: 8.45 min.; purity: 10095; MS (m/z): 434 (MN. shsh s 7.AA 1h42-(2,2-Dimethyl-3-oxo-AN- Analogously to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-YH2-( 3-Hydroxyphenyl)-2,4- benzyl 1,4 |oxazin-6-yl)-5-fluoro-MA-pyrimidinediamine, 42-(2,2-dimethyl-3-oxo-4H-benz|1,4oxazin- 6-yl)-5-fluoro-M4-h » (indazolin-b-yl)-2,4-pyrimidinediamine (indazolin-b-yl)-2,4-pyrimidinediamine is obtained as a result of the resection of 2-chloro-5-fluoro - M. p (K935440) (inpasolin-b-iya)-4-pyrimidinamine and 6-amino-7,2-dimethyl-4H-benz(1,4)oxazin-3-one. /H

NMR (0М5О0-46): 5 10.57 (5, IN), 9.80 (5, IN), 9.44 (in, IN), 8.12 (0, 1Н, 7-44 Hz), 7 .99 (5, 1H, 7.82 (5, 1H), 7.66 (y, IN, 2-8.5 Gy), 7.50-7.47 (49, IN, 7 2.5 and 8.5 Hn), 7.20 (44, IN, З- 2.5 and 8.5 Hz), 7.06 (5, 1Н)), 6.76 (4, 1, 1- 8.5 Гм), 1 ,34 (5, 6H). LC/MS: retention time: 8.26 min.; purity: 9595; MC (m/z): 420 (MN). so 7.4.428 M4-(3,4-dimethoxyphenyl)-5-fluoro-M2- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-(indazoline -5-1l)-2,4-pyrimidinediamine of pyrimidinediamine, M4-(3,4-dimethoxyphenyl)-5-fcor-M2-(indazolin-5-1L)-2,4-ko (K935441) pyrimidinediamine is obtained as a result of the reaction 2-chloro-M-(3,4-dimethoxyphenyl)-5-fluoro-4- (Ce) 42) co 60 b5 of pyrimidineamine and 5-amino ndazoline. NAM (oM50-46): 5 12.82 (5.18), 9.17 (5.18), 9.115, 18), 8.16 (5, 1H), 8.04 (4, IN, /- 3.8 Gy), 7.79 (in, 13), 7.43 (4, 1H, 3-8.5 Hz), 7.35 (4, 1H, 7/2 8.8 Hz), 7, 28-7.23 (t, 2H), 6.90 (4, IN, 7-8.5 Gy), 3.76 (z, ZN), 3.62(5.3H).. LC/MS: retention time: 7.06 min.; purity: 10095; MS (m/z): 381 (MN). 7.4.429 M442,2-dimethyl-3-oxo-4H- similar to the preparation of M4-4(3,4-etiphenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4. gasoline 1,4 |oxazin-b-yl)-5-fluoro-M2-(1-(2-|pyrimidinediamine, M4-(2,2-dimethyl-3-oxo-4H-benzyl I 4 oxazin-b-yl) -5-fluoro-M2-(1-(2-methoxy-4-methoxy-4-methoxycarbonylbenzyl)indazolin-b-yl)-2,4-pyrimidinediamine is obtained in methoxycarbonylbenzyl)indazolin-b-yl|- | as a result of reaction 2 -chloro-M-42,2-dimethyl-3-oxo-4H-benzi 1,4oxazin-b-yl)-5-fluoro-4-2,A-pyrimidinediamine (935442) pyrimidineamine and b-amino-I1-( 2-methoxy-4-methoxycarbonylbenzyl)indazoline. H NMR (rm50-4b): δ 10.72 (5, 18). 10.19 (g 5, 2H), 8.24 (4, 1H, 12 4, 7 Hz), 8.00 (4, IN, 12 09 g), 7.85 (5, 1), 7.64 (0, 1H, 2- 8.5 Hz), 7.444, 1H, 1- 1, 8 Gy), 7.40 (da, 1H, )- 1.7 and 5.0 Gy), 7.264, ЗН, 1- 1.7 and 8.8 Gy), 7.21 (4, 1, 12 1 .8 H), 6.81 (9, 1H, 1 8.5 Hz), 6.76 (4, 1H, 1- 8.0 Hz), 5.39 (5, 2H), 3.8 (5 , ZNI), 3.80 (5, ZN), 1.34 (5.6H). LC/MS: retention time: 170 12.04 min.; purity: 10096; MS (m/z): 598 (MA). 7.A.430 Salt of p-toluenesulfonic acid M4-(3,4- Analogously to the preparation of the salt of benzenesulfonic acid 144-(2,2-dimethyl-3-oxo-4H-dichlorophenyl)-5-fluoro-M241- benz|1,4oxazineb -yl)-5-Ffluoro-Ma-(ndazolin-b-yl)-2,4-pyrimidinediamine, p-methylindazolin-b-yl)-2,4-toluenesulfonic acid m4-(3,4-dichlorophenyl)-5 -fluoro-M2-(1-methylindazolin-6-1l)-2,3-pyrimidinediamine (935443) pyrimidinediamine is obtained as a result of the reaction of M4-(3,4-dichlorophenyl)-5-fluoro-M2-(1-methylinlazolin-b -yl)-2,4-pyrimidinediamine and p-toluenesulfonic acid. "H NMR (0M50-dbu 810.12 (5, 1H), 9.92 (5, 18), 8.29 (4, 1H, 3: 4.1. Gi), 8.09 (5, IN) , 7.93 (5, 18), 7.88 (5, 1H), 7.74 (4, IN, 1-8.5 Gy), 7.66 (4, IN, 7- 8.5 Hz) , 7.55 (4, IN, 4-2: 8.8 Hz), 7.46 (4, 2H, 12 7.9 i), 7.20 (4, 1H, 32: 8.5 Hz), 3.82 (5, ZNU), 2.27 (5, ZN). LC/MS: retention time: 8.39 min.; purity: 10025; MS (m/z): 420 (MN), LC/MS : retention time: 13.48 min.; purity: 9795; MS (m/z): 404 (MH) 7.4.431 Ma-(3,4-dichlorophenyl)-5-fluoro-M2-(2-) Similar to preparation M4 -(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-methylindazolin-b-yl)-2,4.pyrimidinediamine, M4-43,4-dichlorophenyl)-3-fluoro -M2-(2-methylindazolin-b-yl)-2,4-pyrimidinediamine (K935444) pyrimidinediamine is obtained as a result of the reaction of 2-xpor-14-(3,4-lichlorophenyl)-5-fluoro-4-pyrimidinamine and 2- methyl-b-aminoindazole." H NMR (PM5O-46): δ 9.59 (5, 18), 9.33 (5, 1H), 8.204, 1H, 1-5 3.8 Hz), 8.16 (5, 1H), 8,100 1, 1-23 Hz), 7,975, 1), 7,94 (4 1H, 3 2,3 and 8,8 g), 7,534, 1, 2- 8,5 Hz), 7 ,51 (4, 1H, 2 8.8 Gy), 7.1 9 (44, 1H, 15 1.2 and 8.8 Hz), 4.08 (5, ЗН). LC/MS: retention time: 12.08 min.; purity: 10095; MS (m/z): 404 (M 7A ZI M4A-(2,2-dimethyl-3-oxo-4H- Analogous to the preparation of M4-(3,4-ethylenedioxyphenia)-5-fluoro-M2-(3-hydroxyphenyl) -2,4- benz( and Zoxazin-6-1l)-5-fluoro-M2-2-pyrimidimidiamine, M4-(2,2-dimethyl-3-oxo-4H-benz 1,4 foxazin-b-yl) -5-fcor-M2-02-methylindazolin-b-yl)-2,4-methylindazolin-6-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M-(2,2-se pyrimidinediamine ( K935445) dimethyl-3-oxo-4H-benz|1,4|oxazin-b-yl)-3-fluoro-4-pyrimidinamine and 2-methyl-b-aminoinnazole. /"H NMR (OM5O0-46): 6 10.77 (5, IN), 10.69 (5, 18), 10.65 (5, 1), 8.35 (4, o 1H,2- 5 ,3 C), 8.31 (5, 1H)), 7.86 (5, 181), 7.04 (4, 1H, 2-2 8.8 Hz), 7.40 (5, 1H), 7.19-7.15 (t, 1, 7.054, 1, 7- 1.5 and 8.5 Gy), 6.90 (4, NO, 3-2: 8.5 Hz), 4.12 ( in, ZN), 1.40 (5, 6NU.

LC/MS: retention time: 8.93 min.; purity: 10095; MS (m/z): 434 (MIR). 7.4.433 Ma-(3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similarly to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-(2-methylindazolin-b-yl)-2,4-pyrimidinediamine, 1M4-(3-chloro -4-methoxyphenyl)-5-fluoro-M2-(2-methylindazolin-b-yl)-2,4-(Che) pyrimidinediamine (935446) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M-(3-chloro-4 -methoxyphenyl)-5-fluoro-4-pyrimidinamine and 2-methyl-b6-aminoindazole. "N Pits (0M50-46): 5 9.34 (5, 1, Ge»! 9.22 (5, NU, 8.14 (5, 10), VL (4, EN, 1- 3.8 Gy ), 8.03 (5, 1H), 7.84-7.79 (t, IN), 7.73 (6 1H, 1-2.5 Hz), 7.508, 1H, 259.1 g), 717 (4, 1H, 32 8.9 Hz), 7.15 (4, IN, 1- 9.0 Hz), 4.06 (5,

ZNO), 3.88 (5, ZN)), 3.858 (5, ZN). LC/MS: duration of absorption: 9.29 min.; purity: 9795; MS or! (m/z): 399 (MN). 7.4A34 M4-(3,4-dichlorophenyl)-M2-(2-(2- Analogous to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4- sem ethoxycarbonylethyl) )indazolin-5-yl|-5- pyrimidineliamine, M4-(3,4-dichlorophenyl)-M2-(2-O2-ethoxycarbonylethyl)inlazolin-5-1l)-5-

Fluorine-2,4-pyrimidinediamine (K935447) Fluorine-2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M-(3,4-dichlorophenyl)-5-s fluoro-4-pyrimidineamine and 5-amino-2- (2-ethoxycarbovilethyl)indazoline, NN NMR (0M50-46): 6 10.18 (5, NN), 9.82 (5, IN), 8.25 (y, 1H, /- 4.7 Gy), 8.23 (5.1), 8.07 (5, NU, 7.84 (5, 1H0, 7.72 (y, 1H, 1- 8.8 Hz), 7.57 (d, 1H, 12 94 H), 7.52 (y, 18, 22 8.8 Hz), 7.29 (6, 18, 12 9.4 G1i), 4.63 (6, 2H, 7- 6.4 G i) . MS; retention time: 12.53 min.; purity; 9595; MS (m/z): 490 (MN. 7.4.435 744-(2,2-dimethyl-3-oxo-4H-) Analogously to the preparation of M44(3, 4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-benz(1,Poxazin-b-yl)-M2-124(2-pyrimidinediamine, M4-(2,2-dimethyl- 3-oxo-4H-benzi 1, Yoxaziv-6-1l)-M2-(12-(2-ethoxycarbonylethyl)indazolin-5-yl1-5-ethoxycarbonylethyl)inlazolin-5-yl|-5-fluoro-2,4 -pyrimidinedimine is obtained as a result of the reaction of fluoro-2,4-pyrimidinediamine (935448) with 2-chloro-M-(2,2-dimine ethyl-3-oxo-4H-benz| 1,4 (oxazin-b-yl)-5-fluoro-4-pyrimidinamine and 5-amino-2-(2-ethoxycarbonylethnyl)indazoline. "H YAM? (1M5O-45): 5 19.80 (in, IN), 10.46 (5, 1), 10.25 (5, 1H)), 8.24 (y, IN, 3- 5 ,0 Gy), 8.19 (5, 1H), 7.79 (5, 1H), 7.54 (4, 1H, 15 9.1 "» Gy), 7.23 (8, 3H, 3- 91 Hn), 7.19 (v, 1), 6.88 (y, 1H, 22 9.1 Gy), 4.61 (6 2H, 12: 6.4 Hz), 4.03 y (YAN, 3-70 v), 3.00 (6 2Н, 256.4 Hz), 1.364566Н), 111 (0 ЗН, - 7.0 Г). RHUMS: length of stay; 8.96 min.; purity: 95955 MS (m/z): 520 "mn 7.4. 436 5-fluoro-M4-(4-fluoro-3-methoxyphenia)-M2- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-

KE-methylindazolin-6-yl)-2,A-pyrimidinediamine, 5-fluoro-M4-(4-fluoro-3-methoxyphenyl)-M2-(1-methylindazolin-6-yl)-2,4-o pyrimidinediamine ( 3935449) pyrimidinediamine is formed as a result of the reaction of 2-chloro-5-fluoro-M-(4-fluoro-3-methoxyphenyl)-4-pyrimidinamine and I-methyl-b-aminoindazoline. "H NMR (0M5O0-45): 5 . 10.61 (5, 1H). 10.52 5, 18), 8.37 (I, 1H, 7- 5.2 Hz), 7.96 (5, PN), 7.79 (8, PN), 7.66 (Я, 1Н, 3 ko -y 7 42) ko 60 b5

Ya5 pu 76(a4.1HO 33 and 8 Hz), 727-7.12(t, ZNU, 3.755, ZN), 3.55(5.33).. RH/MS:

AI duration of detention; 10.86 min.; purity: 9750; MS (m/z): 383 (MH), 7.4.A37 5-fluoro-Ma-4-fluoro-3-methoxyphenyl)-M2- | Similarly to the preparation of MA-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-tihydroxyphenyl)-2,4-(-methylindazolin-6-yl)-2,4-pyrimidinediamine, 5-fluoro-M4-( 4-fluoro-3-methoxyphenyl)-5-fluoro-142-(2-methylindazolin-b-yl)-pyrimidinediamine (K935450) 2,4-pyrimidinediamine is obtained as a result of the reaction of 2-chloro-5-fluoro-M-(4 -fluoro-3-methoxyphenyl)-4-pyrimidinamine and 2-methyl-b-aminoindazoline. "H NMR (0OM5O-46): 5 10.18 (5, IN), 10.08 (5, 1), 8.28 (5, 1H0), 8.26 (b, IN, 3- 4.8 Gi), 7.84 (5, 1H), 7.61 (d, 1H, 1» 9.1 Hz), 7.48 (da, 1H, 2: 2.3 and 8.0 Hz), 7, 38-7.34 (t, 18), 7.18-7.10 (t, 2H), 4.11 (5, ЗН), 3.65 (5, ЗИ). РХ/MS: duration of retention: 9 ,23 min.; purity: 9795; MS (m/3): 383 (MH). 7.4438 144-(3,4-dichlorophenyl)-5-fluoro- M2-1-(3- Anaphogical to the preparation of the salt of benzenesulfonic acid M4- 4(2,2-dimethyl-3-ocoo-4H-hydroxypropyl)indazolin-5-1l|-2,4- benzyl 1,4|oxazin-6-1l)-5-fluoro-Ma4-(indazolin-b- yl)-2,4-pyrimidinediamine, perform the pyrimidinediamine bis pe reaction between M4-(3,4-dichlorophenyl)-5-fluoro-M2-|1-(3-tihydroxypropyl)indazolin-5-1y|-2,4- toluenesulfonic acid salt (935451) with pyrimidinediamine and 2 equivalents of p-toluenesulfonic acid monohydrate.. The pure reaction mixture is concentrated, triturated to a powder with ether and stirred overnight at M". The formed white precipitate is collected by filtration to obtain Ma4-(3.4-dichlorophenyl)-5- fluoro-M2-(1-(3-tihydroxypropyl)indazolin-5-yl) -2,4-pyrimidinediamine bis-petoluol sulfonic acid salt. "NO NMR (0M50-46): 5 10.67 (in, IN), 10.24 (5, 1H), 8.31 94,

IN, 72: 5.0 Hyd), 8.00 (5, IN), 7.98 (5, 1H)), 7.79 (5, IN), 7.69 (8, IN, 1-91 GR ), 7.63 (5, 18), 7.539, IN, 1- B,K Gy), 7.46 (9, 4, 1-- 8.2 Gy), 7.38 (49, 1H, 15 1 ,4 and 8.5 Hz), 7.10 (3, 4H, with: 8.2 Gy), 4.45 (5, 2H, 3-67 Go), 3.39 (0, 2H, 1 6, 7 Hm), 2.27 (5, 6H), 1.96 (a, 2H, 1-2 6.7 Hn).

PH/MS: retention time: 13.52 min.; purity: 10095; MS (m/z); 404 (МН. 19 74439 М4-(3,А-lichlorophenyl)-5-fluoro-М2-12-|2- Similar to the preparation of М4-(3,4-ethylenedioxyphenyl3-5-fluoro-М2-|34(М- ( M-methylaminocarbonyl)ethyleneindazoline- | methylamino)carbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine, M4A-(3,4-dichlorophenyl)-5-5-yl)-2,4-pyrimidinediamine (KU35452) fluoro-M2-12-12 -(M-methylaminocarbonyl)ethylindazolin-5-yl)-2,4-pyrimidinediamine is obtained as a result of the reaction M4-(3,4 dichlorophenyl)-M2-(2-(2-ethoxycarbonylethyl)indazolin-5-yl1-5-fluoro -2,4-pyrimidinediamine and hydrochloryl methylamine. Hz), 8.07 (I, 1H,1- 2.6 Go), 8.02 (5, IN), 7.89 (5, KNU), 7.83 (dB IN, 72 4.4 Hn) , 7.80-7.77 (t, 2NYU), 7.45 (y,

IN, 2- 8.8 Hyd), 7.43 (4, IN, 72 8.8 Hz), 7.29 (44, IN, 2-5 2.3 and 8.8 ih), 4.51 С , 28, 26.7 Gy), 2.69 (1, 2H, 1- 6.7 Gy), 2.47 (4, ZN, 3- 4.4 Gy). PH/MS: retention time: 9.50 min.; purity: 9395; MS (m/z): 475 (mi. 7.4.540 Ma4(2,2-dimethyl-3-oxo-4H- Analogously to the preparation of M4A-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-I13-(K - benz|1,4)oxazin-b-yl)-5-fluoro-M2-42-methylaminocarbonylmethyleneoxyphenyl|-2,4-pyrimidinediamine, M4-(2,2-dimethyl-3-oxo-

IdA- "4H-benz(1oxazin-6-yl)-5-fluoro-M2-12-H2(MU-methylaminocarbonyl)ethyl)indazolin-5-yl-methylaminocarbonyl)ethyl)ndazolin-5-.2,4 -pyrimidinediamine is obtained as a result of the reaction M4-(2,2-dimethyl-3-oxo-4H-cyl-2,A-pyrimidinediamine (5935453) benzyl 1,4 oxazin-5-yl)-m2-12-(2- ethoxycarbonylethyl)indazoline-5-1l|-3-fluoro-2,4» ptyrimidinediamine and methylamine hydrochloride. I NMR (pM5O-46); b 10.63 (5, 1H), 9.31 Ge) (5, 180), 9.01 (5, 180), 8.06 (8, 14, 3--3.5 Ge), 8, 02 (5, 1H), 7.96 (5, 1H)), 7.87 (i, 1H, 7: 4.4 Hz, 7.434, 1H, 7 8.8 Hz), 7.33-7.25 (t, ЗН), 6.88 (4, 1Н, 4- 8.5 Hz), 4.53 1, 7Н, 1-2 6.7 Hy), 2.73 (02Н, 1- 6.7 Gy), 2.53 (6, ZN, 12 4.4 Gy), 1.41 (8, 6H). PH/MS: retention time: 7.19 min.; purity: 10096; MS (m/z): 505 (MN. 7.4.441 M44(3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(3,4-ethylenedioxyphenyl)-5-fluoro-M2- (3-hydroxyphenyl)-2,4-(Ce) (1-methylindazolin-5-1l)-2,4-pyrimidinediamine, M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M24(i-methylindazolin -5-yl)-2,8- pyrimidinediamine (К935458) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-M-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidinamine and 1-methyl-5-aminoindazole . "H NMR (OM5O-46): 6 19.29 (5, 18), b" 10.18 (c, IN), 8.24 (y, IN, 7- 5.0 Hz), 7.89 (5, 18), 7.86 (5, 15), 7.74 (9, 1H, 1--2.3 Hz), 7.60 (FIN, Gu, 7.54 (44, 1H, 1- 23 and 8.8 Hz), 7.39 (44, 1H, 12 2.0 and 9.1 g), 7.094, 1H, "-- 3-91 Gu, 4.00 (5, ZA), 3, 83 (5, ZN). RH/MS: retention time: 9.92 min., purity: 98;

MS (m/z: 401 (Mn. sch 74442 Ma44(3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similar to the preparation of M4-(3 4-styrenedioxyphenyl)-5-fluoro-M2-(3- tihydroxyphenia)-2,5-(inlazoline5-yl)-2,4-pyrimidinediamine pyrimidinediamine, MA-(3-chloro-4-methoxyphenyl)-5-fluoro- M2-(indazolin-5-11)-2,4-

Zo (8935459) pyrimidinediamine is obtained as a result of the reaction of 2-chloro-1M-(3-chloro-4-methoxyphenyl)-5-he) fluoro-4-pyrimidinamine and 5-aminoindazoline. TIA NMR (0M50-46): d) 9.59 (5, 18), 9.40 (5,

TN), 8.10 (9, 1H, 324.1), 7.97 (in, TNU, 7.87 (5, 1H), 7.79 (4, 1H, in 2.3 Go), 7, 60 (44, 1, 1- 2.3 and 8.8 5), 7.42 (5, 2NI)), 7.08 (4, IN, 1- 8.8 Gy), 3.84 (5, ZN). LC/MS: retention time: 8.84 min.; purity: 9495; MS (m/z): 388 (MN). 74443 M4-(3-chloro-4-methoxyphenyl)-M2-1H1-(2- Analogous to the preparation of 44-(3,4-ethylenedioxyphenyl)-5-fluoro-M2-(3-hydroxyphenyl)-2,4-" ethoxycarbonylethyl )indazoline-5-1l1-5-pyrimidinediamine, M4-(3-chloro-4-methoxyphenyl)-M2-| 1-(2-ethoxycarbonylethyl)indazoline-5-fluoro-2,4-pyrimidinediamine (5935460) and 1-5-fluoro-2,4-pyrimidinediamine are obtained as a result of the reaction of 2-chloro-M-(3Z-chloron4» with methoxyphenyl)-5 -fluoro-4-pyrimidinamine and 5-amino-1-(2-ethoxycarbovilethyl)inlazoline. with 'N YAM? (M 50-46): 6 10.41 (5, IN), 10.30 (5, 1H)), 8.27 (4, IN, 1- 5.3 Hyd), 7.93 (in, IN ), 7.83 (5.1), 7.73 (а, 1, 1-23 Hz), 7.67 а, 1Н, 3- 8.8 Hz), 7.55 (49, 19, 3 2 ,3 and 8.8 Go, 7.39 h (44, 1H, 7-23 and 8.8 Gy), 7.108, IN, 12 8.8 Gy), 4.59 (6, 2H, 12 6.4 Hz) . 7.0 Gy). PH/MS: retention time: 11.20 min.; purity: 9695; MS (m/z): 488 (MN). 74444 Ma-3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similarly to the preparation of M2-(3,4-ethylenelioxyphenyl)-5-fluoro-Ma-|4(2-hydroxy-15 (1-(3-tihydroxypropyl)indazolin-5-yl|-2,4- | dimethylethyl)phenia | -2,4-pyrimidinediamine, M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-H1-(3" tarimidinediamine (935481) hydroxypropyl)indazolin-5-yl)-2,4-pyrimidinediamine is obtained in as a result of the reaction of M4-(3-(o)chloro-4-methoxyphenyl)-M2-(1-(2-ethoxycarbonylethyl)inlazolin-5-yl1-5-fluoro-2,4-pyrimidinediamine and diisobutyllithium aluminum hydride. "H NMR (OM5O0 -46); 5 9.29 (5, 18), ko 9.18 (5, 1H), 8.07 (4, 1H, 7- 3.8 Hz), 8.02 (5, 1), 7 .81 (5, 15), 7.80 (0, IN, 2-23 Hz), 7.65 - (84, IN, 1 2.3 and 8.8 Gm), 7.48 (vrr 4, 2Н , 22: 8.8 Gy), 7.10 (4, 1H, 4- 8.8 Gy), 4.58 (5, IN, 2 4.7 Hz), 4.37 (, 2H, 1- 6 .7 Hz), 3.84 (5, ZN), 3.34 (i, 1H, 1: 6.7 Hz), 1.92 (4, 28.15 6.7 Gy).

РХ/MS: duration of immersion: 9.00 min.; purity: 9595; MS (m/z): 445 (Mn. x) 7.4.445 M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2- | Similarly to the preparation of MA-(3,4-ethylenedioxyphenyl)-5-fluoro-Mm2-13-(M-

П-п4х- methylamino)carbonylmethyleneoxyphenyl|-2,4-pyrimidinidiamine, М4-(3-chloro-4» b» methylaminocarbonyl)ethyl|indazoline-5-methoxyphenyl)-5-fluoro-М2-41-|(24(М -methylaminocarbonylistyl |indazolin-5-1l1-2,4-yl)-2,4-pyrimidinediamine (K935462) pyrimidinediamine is obtained as a result of the reaction M4-(3-chloro-4-methoxyphenyl)- M2-(14(2- ethoxycarbonylethyl )indazoline-5-1l)-5-fluoro-2,4-pyrimidinediamine and hydrochloromethylamine. "H NMR (0MI5O-46): 8 9.31 (5, 1NI), 9.20 (5, 1), 8 .08 (y, 18, 1-4.8 Gy), 8.02 (5, IN), 7.84 (di, 18, 2-4.7 Hz), 7.815, 18), 7.78 (0 , 1H, 7» 2.6 Gy), 7.66 (46, 1H, 1- 2.6 and 91 Gy), 7.49 (6, 1H, 329.3 Hz), 7.46 (8, 1H , 129, Gy), 7.11 (4, IN, 75 9.1 Hz), 4.51 (0, 2H, ze 6.7 Hn), 3.85 (5, ZN), 2.63 (5 , 7Н, 1- 6.7 Hz), 2.50 (8, ЗН, 12 4.7 ГН). LC/MS: duration

GF) retention: 8.60 min.; purity: 9395; MS (m/z): 472 (MN). ko 7.5 The 2,4-pyrimidinediamine compounds presented in the present invention inhibit degranulation mediated by Ese KI 60 receptors The ability of 2,4-pyrimidinediamine compounds to inhibit IdCHE-induced degranulation was demonstrated in a number of cellular assays on cultured human mast cells (CHMS) and (or) cells obtained from mouse bone marrow (BMMS). Inhibition of degranulation was measured at both low and high densities

CELL POPULATION with the help of QUANTITATIVE DETERMINATION of the release of granules-specific factors of tryptase, pstamine and hexosaminidase. Inhibition of the release and (or) synthesis of lipid mediators was evaluated by MEASURING 65 release of leukotriene and TS4, and inhibition of the release and (or) synthesis of cytokines was evaluated using the quantitative analysis of TME-o, 1-6 and 1Y/-13. Quantitative analysis of tryptase and hexosaminidase was performed using fluorogenic substrates in accordance with the description given in specific examples. Quantitative determination of histamine, TME o, 1-6, 1-13 and GTS4 was carried out using the following kits of commercial manufacturers for solid-phase enzyme immunoassay (EGIBA): histamine (supplier "Ittipoyesr", catalog Mo2015, VesKtap SotsMeg), TMEo (supplier, Viozotsgse ", catalog Mo KNSZO11), 1/-6 (supplier "Viozoiigse", catalog Mo KMSOO6T1), 1-13 (supplier "Viozotsgse", catalog Mo KNSO132) and

YTS4 (supplier of "Sautap SNetis!", catalog No. 520211). Protocols for various analyzes are given below. 7.5.1. Cultivation of human mast cells and basophils

Human mast cells and basophils were cultured from SOC4-negative progenitor cells according to the following description | see also the methods set forth in concurrently filed US patent application Mo10/053355, filed November 8, 2001, which is incorporated herein by reference). 7.5.1.1. Preparation of complete nutrient medium ZTEMRKO-34

To prepare complete ZTEMRKO-34 nutrient medium (SM), 75 250 ml of ZTEMRKO-34ltm serum-free medium (ZEM, supplier "sSirsoVvkK!", catalog Mo10640) was placed in a flask for filtering. Into this flask was added 1 ml of nutritional supplement "ZTEMRKO-34 Miigiepi Zirrietepi" (M5, supplier "sSirsoVvki", catalog Mo10641) (the preparation process is given in more detail below). The nutrient vessel was washed with approximately 17 Oml of serum-free medium and this fluid was added to the filter flask. After adding 5 ml of I-glutamine (200 mmol; supplier "Meyyaesy", catalog Mo MT 25-005-SI) and Bml 100X penicillin/streptomycin ("pen-strep"; supplier "NuSiope", catalog Mo 5MZ30010), the volume was proved to 500 ml by adding serum-free medium, and then the solution was filtered.

The most variable element in the preparation of a complete nutrient medium is the method by which the nutrient supplement is thawed and mixed prior to its infusion into the serum-free medium.

Thawing of the nutritional supplement must be carried out in a water bath at a temperature of 37 "C with circular stirring, without swirling and shaking, until complete dissolution. During stirring, it is necessary to monitor whether undissolved lipids remain. If they are present and the solution is not homogeneous, it is necessary to place the additive again in a water bath and continue the mixing process until a homogeneous solution is obtained.

Sometimes this component dissolves immediately, sometimes - after one or two cycles of mixing, and sometimes it does not dissolve at all. If after one or two hours the nutritional supplement does not turn into a homogeneous solution, it should be discarded and a new one thawed. Do not use a nutritional supplement that has a non-uniform appearance after thawing. F 7.5.1.2. An increase in the population of SOC4-cells th

The initial population of COZ4-positive (COZ4Azh) cells, which was quite small (1-5x10 9 cells), was increased to a relatively high number of COZ4-negative progenitor cells (about 2-4x109 cells) using the methodology and nutrient medium described below. SOZ4Ach- cells (from one donor) were obtained from the company (ge) "Aiseiiv" (Berkeley, California). As there is usually some variability in the quality and quantity of cells supplied by this company, the resulting cell cultures were placed in a 15ml conical tube and brought up to a volume of 10ml in complete nutrient medium before use. "

On day 0, viable (refractile) cells were counted, and then the cells were centrifuged at 1200 rpm. Cells were re-suspended to a density of 275,000 cells/ml in a complete nutrient medium containing 200 ng/ml of recombinant human stem cell factor (5SE, supplier, Rergoiesn", "» catalog Mo300-07) and 2 ng/ml of human 1-3 ligand ( supplier "Rergoiesp", catalog /Мо300-19) (hereinafter "- medium СМ/5СЕЛИ-3). Approximately on the fourth or fifth day, the density of the culture was checked by counting cells, and the culture was diluted to a density of 27,500 cells/ml with fresh nutrient medium." SM/ZSELY-3". On approximately the seventh day, the culture was transferred to a sterile tube and cell counting was carried out. The cells were centrifuged at 1200 rpm and resuspended to a density of 275,000 cells/ml in fresh medium "SM/5SELIE.

This cycle was repeated, starting from the day of Mo 0, in total from 3 to 5 times during the period of population increase. "c 20 If it is necessary to re-suspend a large number of cultures contained in several flasks, the contents of all flasks are combined in one vessel before counting cells. This ensures (42) the accuracy of cell counting, as well as a uniform approach to the entire population. Before combining the contents, the flask is checked under a microscope for contamination in order to prevent possible contamination of the entire population. 52 Between 17 and 24 days, deterioration of the culture is possible (ie, 5 to 1095 of the total number of cells die), and population growth slows down. During this period, the cells are monitored daily, as the culture can completely die in just one day. After the deterioration of her condition, the cells are counted and centrifuged at 850 rpm. within 15 minutes and resuspended at a density of 35,000 O cells/ml in complete CM/ZSELIZ medium in order to obtain one or two more divisions of the culture. 60 cells are monitored daily to prevent culture death.

If more than 1,595 cells of the progenitor cell culture die and a certain number of decomposition products are present in the culture, SHUOZ4-negative progenitor cells are ready for differentiation. 7.5.1.3 Differentiation of SHUOZ4-negative progenitor cells into mucosal mast cells

The second phase is performed to transform the grown COZ4-negative progenitor cells into differentiated mucosal mast cells. These mucoid cultured human mast cells (CMCs) are derived from cells extracted from umbilical cord blood and processed to obtain a large population of COZ4-negative progenitor cells as described above. To obtain CO43Z-negative progenitor cells, the culture resuspension cycle was identical to the above, with the exception that the culture was seeded at a density of 425,000 cells/ml and on the fourth or fifth day, about 1595 additional medium was added without counting cells. In addition, the cytokine composition of the medium was changed so that it contained stem cell factor (20 ng/ml) and human recombinant 1-6 (20 ng/ml; supplier "Rergoiesi", catalog

Mo200-06, reconstituted to 10O0µm/ml in sterile acetic acid, 10mmol) (hereinafter referred to as SM/5SELI-6 medium).

Phase II takes about 5 weeks. Cell death and the presence of decomposition products in culture 7/0 are observed during the first to third week; in addition, from the second to the fifth week there is a period during which some part of the culture is not in suspension, but is attached to the surface of the vessel in which the culture is grown.

As during | phase, if necessary to resuspend the culture on the seventh day of each cycle, the contents of all flasks were combined in one vessel before counting cells to ensure uniformity of the entire 7/5 population. Each flask was previously inspected under a microscope to detect contamination and prevent contamination of the entire population.

When combining the contents of the flasks, approximately 7595 of the volume of the flasks was poured into a common vessel, while about 1Oml remained in the flask. The flask with the remaining liquid was sharply tapped laterally to release the cells that had attached to the surface. Repeated tapping was carried out at a right angle to the first in order to finally move the cells out of place by 2o.

Before pouring the remaining liquid into the counting vessel, the flask was tilted at an angle of 45 degrees for several minutes. Before seeding in a volume of 35-5bb0ml per flask (at a density of 42500 cells/ml), the cells were centrifuged at 950rpm for 15 minutes. 7.5.1.4 Differentiation of SHUOZ4-negative progenitor cells into mast cells of connective tissue with

A proliferative population of SHUOZ4-negative progenitor cells was prepared according to the method described above and processed to form a tryptase/chymase-positive phenotype (connective tissue). At the same time (8) used methods similar to those described above for mast cells of mucous membranes, with the exception of adding II/-4 instead of I-b to the culture medium. The obtained cells are typical for connective tissue mast cells. "с зо 7.5.1.5 Differentiation of SOC4-negative progenitor cells into basophils

A proliferative population of SOC4-negative progenitor cells was prepared according to the method described above in b» section 7.5.1.3 and used to form an increased population of basophils. COZ4-negative cells "- were processed by a method similar to that described above for mast cells of the mucous membranes, except for the addition of 1-3 (20-5Ong/ml) instead of II-6 in the culture medium. c 7.5.2 IDE activation of low-density SNMS: analysis of tryptase and I TS4 co

In two 9b-well tablets with round-bottomed wells (Sauviag model 3799) add a volume of solutions of the prepared compounds or control samples prepared in MT (137 mmol Mass, 2.7/mmol KS1, 1.8 mmol

Sasi", 1.0 mmol Mosi", 5.bmmol glucose, 20 mmol M-2-hydroxyethylpiperazine-M-2-ethanesulfonic acid (pH 7.4), 0.195 bovine serum albumin, (Zidta A4503)) with a content of 295 MeOHn and 195 Mo. Then the CNMS are separated in a centrifuge (980 rpm, 10 min) and re-suspended in a pre-heated MT environment. Next, 5 μl of c cells are poured into each 96-well plate. Depending on the degranulation activity of each of the individual CNMS donors, 1000 to 1500 cells are placed in each well. Then they are mixed four times with the next one with incubation for 1 hour at a temperature of 37 C. During incubation, a solution of 6bH anti-9eE (anti-human rabbit immunoglobulin IZE) is prepared (mg/ml, supplier "VeiNui I Arogayogiev", catalog Mo A8VO-109A ), diluted 1:167 in MT buffer solution). Cells are stimulated by adding 25 μl of 6X anti-ID9E solution to

Go! corresponding tablets. Add 25 μl of MT to the control tubes that are not subject to stimulation. After adding anti-immunoglobulin E, the mixture is mixed twice and incubated at 37 2C for 30 minutes. During the 30-minute incubation, prepare a solution of 20 mmol of broth with tryptase substrate |(2-AiIa-I uh-Aga-AMSOS.2TREA; - Epgute Zuzietv Rgodisiv, KhaMS-246)| 112,000 in a buffer solution for the quantitative analysis of tryptase (0.1 M 0 M-2-hydroxyethylpiperazine-M-2-ethanesulfonic acid (pH 7.5), 10956 m/v glycerol, 1 μmol of heparin (Zidta o H-4898) 0.0195 Mamze »|. The tablets are centrifuged at 1000 rpm for 1 min to separate the cells. Then

GIs transfer 25 μl of the supernatant to a 9b-well black-bottom tablet and add 100 μl of freshly diluted tryptase substrate solution to each well. Incubate ZOhv at room temperature. Using a spectrophotometer to read the tablets, determine the optical density of the tablets at 355nm/4bOonm.

Quantitative analysis of leukotriene C4 (I 74) is also carried out using EGISA kits on properly diluted samples of the supernatant (determined empirically for the cell population of each of

F) donors so that the measurements of the samples are within the standard curve) in accordance with the manufacturer's instructions. ko 7.5.3 Activation of CNMSOS using IDE at high cell density: assays for degranulation (tryptase, histamine), leukotriene (I TC4) and cytokine (TMRairna, II -13) 60 Cultured human mast cells (CNMS) are sensitized for 5 days by with the help of II-4 (2Ong/ml), stem cell factor (20Ong/ml), 1-6 (20Ong/ml), and I(DdDE human (SR 1035K, supplier "Sogih Viospept", 100-BOOng/ml depending on generation) in a complete nutrient medium. After sensitization, the cells are counted, centrifuged (100 rpm, from 5 to 10 min) and resuspended at a density of 1-2 x 10 cells/ml in MT buffer solution. Add 10 μl of the cell suspension to each well and 100 μl of the prepared solutions compounds. 65 The final concentration of the medium is 0.5960 M50. Incubate at 372 (5956 СО) for 1 hour. After an hour of treatment with reagents, B6X cells are stimulated with anti-IZE. Mix the wells with cells and leave the plates for incubation at 372 (5956 СО") for one hour After incubation for one hour, centers fuse the cells (1 Ohv, 1000 rpm) and take 200 μl of the supernatant from each well, while acting carefully so as not to touch the sediment. The tablet with the supernatant is placed on ice. When performing an operation that requires 7 hours (see

Below), tryptase activity of the supernatant diluted in a ratio of 1:500 is determined. Re-suspend the cells in 240 μl of complete nutrient medium containing 0.595 ЮОМ5О and the appropriate concentration of the compound.

CNMS cells are incubated for 7 hours at 37 9 (595 СО). After incubation, the cells are centrifuged (1000 rpm, 10 min.), 225 μl are taken from each well and stored at a temperature of -809C until ready for EGISA analysis. The EGISA assay is performed on appropriately diluted samples (determined 70 empirically for the cell population of each donor so that sample measurements are within the standard curve) according to the manufacturer's instructions. 7.5.4 Activation of VMMS with the help of IDdE at high cell density: analyzes for degranulation (hexosiminidase, histamine), leukotriene (I TC4) and cytokine (TMRairna, 1-6) 7.5.4.1 Preparation of conditioned medium of UENI

Conditioned MENI medium was obtained by growing mouse myelomonocytic cells

MUENI-ZV (Collection of American Type Cultures, Rockville, Maryland) in Eagle's medium (Eadiev), modified according to Iskov's method (supplier "Mediayesi", Hernandon, Virginia) with the addition of 1095 fetal calf serum, inactivated by heat treatment (supplier "KN Viozsiepsev", m.

Kansas City, Missouri), 5bOmmol 2-mercaptoethanol (supplier "Zidta", St. Louis, Missouri) and 100 IU/ml penicillin-streptomycin (supplier "Meyia(esnp")) in an incubator at 372C in a humidified environment of 596 CO2/9595 air . The initial cell suspension was seeded at a density of approximately 20,000 cells/mL and then split 1:4 every 3-4 days for two weeks. Cell-free supernatants were collected, aliquoted, and stored at -802C until needed. 7.5.4.2 Preparation environment of the VMMS of the village

The VMMS medium consists of 2095 UMENI conditioned medium, 1095 calf embryonic serum, inactivated by heat treatment (supplier "UNK Viozsiepsev"), 25mMmMol

M-2-hydroxyethylpiperazine-M-2-ethanesulfonic acid, pH 7.4 (supplier "Zidta"), 2 mmol I-glutamine (supplier "Mediaesi"), 0.1 mmol substitute amino acids (supplier "Mediahesp"), Tmmol sodium pyruvate ( supplier "Mediaesi"), 5 ΩmMmol of 2-mercaptoethanol (supplier "Zidta") and 10010/ml. "On penicillin-streptomycin (supplier "Mediaesp") in medium KRMI1640 (supplier "Mediaesp"). To prepare the medium of VMMS, all components are combined in a sterile vessel for filtration of IU. and passed through a О0.2μm filter before use. h- 7.5.4.3 Protocol

Bone marrow mast cells (BMMS) are sensitized overnight with murine stem cell factor sia (2 ng/ml) and monoclonal anti-DNA (1 TONg/ml, Siope ZRE-7, supplier "Zidta", catalog number 0O-8406b) (with medium VMMS at a cell density of 66 x 10 cells/ml. After sensitization, the cells are counted, centrifuged (1000 rpm, 5-10 min.) and resuspended at a density of 1-3 x 10 cells/ml in a buffer solution

Mt buffer. Add 10 μl of cell suspension to each well and 100 μl of compound solutions. The final concentration of the filler is 0.595 OM5O. Incubate at 372С (5956 СО») for 1 hour. After 1 hour of treatment with compound 70, cells are stimulated with 6X stimulus (bong/ml DNA-protein complex-bovine serum albumin). Mix wells with cells and incubate the plates at a temperature of 372 (595 CO") for one hour. After one hour of incubation, the cells are centrifuged (1 rpm, 1000 rpm), 200 μl of supernatant are taken from each well; while acting carefully so as not to touch the sediment, and move it into a clean test tube or 96b-well plate.

Place the tablet with the supernatant on ice. During the operation, which takes 4 to 5 hours (see below), 15 the hexosimidase test is performed. Resuspend the cells in 240 μl of UMEI nutrient medium, which contains 0.596 OM5BO and the corresponding concentration of the compound. Incubate VMMS cells for 4-5 hours at a temperature of 372 (595 СО"). After incubation, the cells are centrifuged (1000 rpm, 1 rpm), 225 μl are taken from each test tube and stored at -802C until EGI5ZA. EGISA is performed on 5p of properly diluted samples (determined empirically for the cell population of each of the donors with (se) that sample changes are within the standard curve) according to the manufacturer's instructions.

FO Analysis of hexosaminidase: 5µl of hexosaminidase substrate (4-methylumbelliferyl-M-acetyl-p-Ob-glucosaminid; 2mmol) is poured into each well of a black 96-well tablet for analysis. Add 50 μl of the supernatant of VMMS cells (see above) to the hexosaminidase substrate, keep it at 372C for 30 minutes and analyze the plate after 5, 10, 15 and 30 minutes on a spectrophotometer. 7.5.5. Activation of basophils with the help of IDE or house mite allergen: analysis of histamine release (F) Analysis of basophil activation was performed using whole peripheral blood of a person taken from donors suffering from allergy to house mites; most of the red blood cells were removed by dextran precipitation. Human peripheral blood was mixed in a ratio of 1:11 with Z9o dextran 1500 and erythrocyte sedimentation was carried out for 20-25 minutes. The upper fraction was diluted with three volumes of Dulbecco's phosphate-buffered saline and the cells were centrifuged for 15 minutes at 1500 rpm at room temperature. The supernatant was removed with an aspirator and the cells were washed with an equal volume

Mt buffer. At the end, cells were resuspended in MT-buffer containing 0.5 OM5O in the initial volume of blood. 8 µl of cells were mixed with 200 µl of the compound in the presence of 0.590 µM5O, in triplicate, in a 9b6-well b5 plate with deep wells for the cultivation of tissue cultures. A number of doses of concentrates of 8 compounds were analyzed, as a result of which a 10-point dose-response curve was obtained, which includes the maximum point

(stimulated reaction) and the minimum point (non-stimulated reaction). Incubation of cells was carried out after the addition of compounds, for 1 hour at a temperature of 37 oC, with 5956 CO", after which 200 μl of bh stimulator (μg/ml of anti-SHE (supplier of "Veipu! "Apiidep and Arogayughiev")). Cells were stimulated for 30 minutes at 372С, 596С. The tablet was centrifuged for 10 minutes at 1,500 rpm at room temperature and 8 μl of the supernatant was collected for analysis of histamine content, for which the EGIZA kit for histamine (supplier "Ittipoesp") was used. The EI IZA analysis was carried out according to the manufacturer's instructions. 7.5.6 Results

The results of the analysis of the low-density CNMS populations (Section 7.5.2), the high-density VMMS populations (Section 7.5.4), and the analysis of basophils (Section 7.5.5) are shown in Table 1. The results of the analysis of the high-density CNMS populations (Section 7.5.3) are shown in Table 2. All values in Tables 1 and 2 are expressed in ISvo (in μmol).

The indicator "9999" means ISvo»1Ommol in the absence of measurable activity at a concentration of TOmmol. In most of the analyzed compounds, the IC value was less than 1 µmol, and in many it was observed in the 75 sub-micromolar range. 7.8 2,4-pyrimidinediamine compounds inhibit degranulation mediated by Esu KI receptors

The ability of the 2,4-pyrimidinediamine compounds described in this invention to inhibit Esu Ki-mediated degranulation was demonstrated by the example of compounds K9U21218, K921302, K921303, K940347, KO20410,

KkU27050, K940350, K935372, K920323, K926971 and K940352 in analyzes similar to those given in section 7.5, with the exception that the cells were not pretreated with immunoglobulin E and they were activated with the Bar fragment of rabbit anti-human immunoglobulin dO (supplier "Vetyl I Arogayogiev", catalog Mo

A8O-105). For all analyzed compounds, the values of IC 50) were in the submicromolar range.

Table I

Low density si snMs SyMo snMo snMs snMs Basophils | Besophils. Basophils vMMo vMMe VMS pronounced vMMCsM compound Tryptase Tryptase Tle4 Hexose. Hexose. Histamine Histamine Cystamine Hexose Hexose. histamine itsa TME.alpha ie Ge) aa Go 11717170 US - o« lL---.2---2ИШЩВ-5--2ШШШЩК--2.-Ш- 2-22 5 Ш ( Й х 4. | ( - - yuyu --25--52З352-225- 6 «НЯ 6 6 Л tSL I 6 Е 66 ---- 2 A МН --

Gvvy 0 Z («5 "FOR - " 5 - - -5 .sh.Sh - 4-52 - - - 26 2 - 5.-- - - - - -- -- - - --- - - - Yes There are 2 x 2 - - - - - - -;n Y- - 2 - -- (Se) yujet 1 -------2--2SHVVA---::Й20ЙЙ-62SHISHVKA- I- (IZUT 2 Ж -- Ф кви у 11117yappptpttpNppNtptA- sent TIRES r З-2З- 102 tt TT 1 TT « NI. «-

Ha -5-- 5 F F- 5 (- 22 7 F 2 5 F: 6 t 0 --85В--Х2--522---5-588Ш2-5-5Ш--5Ш2---55-- - frames! 0/7 11110710 1.171717 52203341 1 17 3

Rava --------Н-ШН- I I Z ТЯ 6 5 55 5 :.-- - 5 5- s as zv rt tr r 2 5 so 908697 99991 999 shDsh shХХКК | WHY M FRI Fri

Govorogz, | 9909995 1 ---- 5 5 5 t I o Y l 5 o piynyshini tt vysh 20 I yazoyumi | beat | 8 10101101) ot 01101011 syu» | hatch | 095 o | From rya lake | I am | (HER F (17703017 77717 7 1717777 s year; | 0 | 56 | (M 1... 1 ..D.D15.5.DYUZH 2 117.4. 77177771 17

K50945 1 0255 | b. 00001 kN NYODIVNNU NEWS Heights 1 "from | kobogya, | 2393 | 995 | шЩ(І юКхф) THEY MUST UNN write write pi i " koo9zyaV Shk shik wa v pila prya roya nora poru Pr non nia ko09249 9999 9999 PO 77217701 OD 890925 nickname: nen vysh pnya SHA VO OO PNYA shsh UNO POHANNN so ko - (Se) (42) ko 60 b5

Table 1: sn sht sn sn snMs snMss Basophils. Basophils Basophils of the Navy of the Navy of the Navy of the Navy of the Navy

Analyzed! ante-ivE | Knomishna antique | Yukomycin | anti-IvE Tovomyshny Jak klishch Isnodrachn zntn-IvE ze teri vne compound | Tryptase | Tryptase 14 Hexose. Keksoz. Histamine histamine histamine Hexose exos. histamiv -alpha ee t r A рР- 2 o,

МШЗТШ--- 5 3 5 5 5 ж 7 МШШ-ЗУ-Ж-Й55-5-5-25Й252Б8К---52ШGB71-5-05-- holes te571 in 17777711 1 МЖШШШ- 252 62 56565 32 ( ( 5 (Ж Ж Ж ИЗ 5 75 7 yuyu et t 1 r 1 1 vv! with 1 yayu 77771111 20200120Ш2020100Ш00202020020-00 И--

Ge | и 71 яю 17111202 -05--2-О2ШЗ530-О0ОО

And keyuvy | 2557 55 111 12020012З-2-52005--00-2-2-ИШЖ0IZZ0520Й202Ш2IZ5Й-0ШЦШШКБШИШ-ШШВЦРЖААЕШЦСUTУмВНА-"-

They work for 71 le" 17 2 2 A A-- 2 6 5НЧНСЛО L "LZ LU

PETTI NGU NI: ZV NNYA PON VONO KONYA POLON: FIBER NOV NO NANNYA COLUMNS NN ON tyu Iv m | yayu 17777212 525251 .« . LO L-6 Ж (Ж 6 ( « (Ж ЖХ «"-ЖЖХ« «« Ж (Ж (Ж « 9 Ж« "9 "LYAL L 9 Ll 5, cast tv r 2 2 R 2 25 RA A LO

ЮМЗХТЙ- 6 (ШЖЖЖ.ЖЙ Ж OK « ; 6 ЖХ В- - 6 2-2 2 2 2ХОА- 252 ШВИ 5 6 ( (;6Я; Ш Z Я « «Ж (UL 73

PETRA ZY US FOR GROSS NEW NEW NEW NEW NEW CAPTURES

Veovi" 301 9999 1 B 25-62 -2ВАШЩ8ШШШШ-ШШШШШЩШШШШШШШШШШШШШН- kit! call | 55777111 ИЖШШЗВ-5Б55Й- 5385-33 3-552ЗЗ0--- ns: ТИНИ: НН МНН НИМИ ПНЯ НН ПОЛОН POLO ПН поля о ох поро пон ее я -ОШ-ШВШХВА-2ШВА 2 2 -ШЖЗБЗБШБИЗВШШ--Ш25ШЩЩKBEBШ ЙОО Я ЕЕЯЯ 4Ll lo 18 you Ш5Й---- BY ЗММЗЗ--5БШКААЙШШЗКНЯЗШБ З 5- 05353235 pit PLOV NM NOT non -p070752Й2Й3Й- ee! ve ze 1 OO 2 "NA-ШЖВ-2ВЗЗА-55-2Ш2В28ВЗ-602-52 252 -052--2IBBINAISH2ZVY3Z- pe t --52ШШБШШШШВАШБ ЗМ Й2ЗШ2ШMM 2 28:53 33-5555ББАШ ША -ШНШШН- potnso SHE NIKA SV UA VA VSE VYN S he 7-1 vov | zkh 1 oyu oo 17700771 vro | both become yy NISNYA PINNY MS POLA SIA THEY PON PANNA NA: Ж NS PON PA Mb PON ke! 21 2 5 12 2 2225122 2 2 12 2

Hook! I 1 I 177171 ШШБШШШЯВБ5ИА- I I J J J Liu « LZ zr tt yy r OO « o

Anne nn

SUT eN O HNN VNS: media COMPLETELY NEW COAOLNLONONNYA POLON NONONNNM VONYANYA VANNY FIELD blue nenya in pnnny --- -

Pr vatlvk Ta pivo plyn --ya t-5-5- s 29 Table 1 sleep o

High density of syMs smo sMs sMe Basophils Basophils vBasophiln vm vMZMs vymov vVMMS vMMsM

Analyzed anti-Ivy | ionomycin | avtn-idE anta-IVE Tonodrachly | anti-TrE) Ionomishchyn | Hut. mite Ionomycin o) znti-ivE zitae sive Sho compound Lyarnptase | Tryptase eats Hexose. Hexose, Histamine Histamine Histamine Hexose Hexose. histamine -alpha euro 1 A 1-1 vart 05 ШБШБШШЩBA5ШБВНВН-АБШВЩВАЕШШШШ2ЗЗК "ОНУгФЯА-ЗАКНА I LZ I o - -- I 130 1-3 --5BVB- 5355 i r t b ve 17771222 1-00 7075-0235 7О-- - 26 I am a man -

PSUETE TA NO YN NE TZN NOM KOLON KONYA KOH NONONNYA KAN KON IMIVZ--IOIZOI- o« «RT - - б т кузие | su 1 571 zi 17225251 2 2 "Z ZLO LO L--202Ш2502--52-202-2Ш2ЙВК58-2ИВЙ-2ШВ- ИИЗ82-5КИ-- vemta and oz z | о 177721 11202002Й--20202010220SHVISHY-2ШЗ01ЦШИЗ-ШВЗ1Ш---Ш2ШВ-Й-Й-Й2З0--- с

Hey! 38 I 1701172 1-220250-2002Ш00Й2-Ш02Ш2ШЙ-02ШШЯ-202Ш0ШВ5Й-02Ш2БЗ0Й-0ШЗВ-Ш2ЗВВМККШКШ-ШЙ howls! 3977 5551 МШЖЖШВО--Ш-ИОИВ38А-И2-И-2-2-00Й2Й2З32-ИИ23532Б--20Й5Ш25З2---7 Й3ИБЩ3Б535- со зво Гееву тяя20-2-5252И2В--5-52IV2--252SHIVSHХ-О2И25-VYZIANВІБВАВА --AT-

Ps NVO NOTES IT MON p0IZY38-5- mon MO MON MON FRI Po POOYA

POTEN IS NOT GUILTY: CALLING THE CAPTURE OF VOLOLAALNYA PON PON AN sewn Co., Ltd." 1711 ш-0ЙВБ53-Ш-О0505- МЙУ-- "pig catching Noah's captivity -ЗБ-8З-- 5656 5 5 - - А 2 - - - - vve sang t t r r R 2 R NO

Skyuztya pere -- IZB--- 7 pe ns shi I-- and IL-- ШЯ ShSHVNK-252-2Ш22--02Ш2- с b яю 1 я 17223121 0Й0- write ШЯ av SHISHY-SHVZB-252SHVZYU6BA--Й5Ш069TIZNEIZVBSHCHOE-- -Ш Ш -0Ш Ш Ш.Ш Я A 8 ИН Ш- « зо г7О-ОИ2035З3 » ШШ- ИМЗ-ШЙ-6250- "АНЯ СС ЮШВШХВ-2ШВБВАШ2Ш2Ш0В8БВЖ-5--7:Д ' svo svo eIIVY 2ShVZ 5 "65 «0l» ON (- 2 ж ж Ж - - 5 yayu | 59 1 МЗБ- я «5 - ШВЕШШВРВ-- vorkhoz | yayu 1 9 11 00535 Ш--- 0-52 p0IZ505-

Gkrim yati 1 3 Ш-ШШ05Й-- И5- со в» 3 И-0505- nyshn nin ko25806 9995 | 9999 li NI PI 2--

Koozvo ШИ ИЗИ2И25Й--ШЗБЗБЙ--ШБ5ВЩЧА--БЩШЩ8Н- 3 - 55ЙВ- t poonoya i 17 | 0Й5-5-- -5Zev ШХВЗ-- shk (se) (4 ko bo 65

Hablinia 1

High density sno snMs sno snMse cm Basophils Basophils Basophils MM vMMs vm vMMe vm vmMmMoeM

Analyzed) anti ivb | Myunomycin | anti-vE anti-IEE | Ionomycin anti-SHE | Mbnomishin | Hut Khlysh | anti-ivE ionomtsshchin | anti-IrE | anti-IVE antn-4vB. antn-IvB compound Tryptase | Tryptase Me Hexose. Hexose. Histamine Histamine Histamine Hexose Hexose, histamine IT TME-elfa tso-6 kezhviyu | 9999 | 999 | !/ | YY YY PI KOLVNNYH PILY PON NNnu VAHNYNN 9 (koki 38 royu 00001111 nin lived SAW FIELDS POLON MYVONOVYN PINNONLNY NIKHONAIVNNNY COCOA NO NOFNN NNYA

VO258I3 go shi | COMPLETE KINNNNNNNNN NK NOVA KN rve ze ov "A. 5 6 5 25 b- LA 5 | There is also 53 ' 8-2K- Ж - '-ф7 - | : (- (| 4 I-- - 4 - I - carried Her 60 |o9999 0011 22717722 (o vzhiya | 9955 | 995 11101110 (took 9999, | 9995 | 01711110 FIELD OF NEWS PINNIINODN KANVA | vzohyaai | v | yayu 11110111 YOU WERE DUST) VYNNYKH POLO PON ko25523 syu -22Й0--5553НН-32----8333-------- treasury | 9999 | yuyu 00001011 piMON POLYN NOKYOVONVNu NOKHOKNNNN.

Ko25824 SV yy yy yy VINY POLYN POLYN POHNNNN. 5999 1995 | 11011 that pgt 1 (ovozhyuzyu | 959991 99 11001111 2-77 Pi PI kog5539 | 9999 | 999 | 1 |. MON PIANINNNNYA CON. toetnoso?onu same! .K925840 | 99991 9999 | | 1 PILY: DUST Ш ши shishШ kova! | 9999 999 8-25525-- - - Я- везхваз | 9999 | 999 | шЩщ 7 253 2 ver -Ш2ШВШШШШВЗ-ШШВБКШШБВА-ШВНВАА--Ш--2ШБЩ--ШВ--ШННН- zr 01111111 5959 | 99950010 ШО I yayu | 1.61171 0777 0.925 Etutnnnnnnaya Passovering of the Nonnnnitsnnnnnnnnnnaya Ponna

Gokdazna | 31995141

And vegaah3 | 999 1 95 | 0100 | oo atts ren and ve Ov 22 "L,---- Жж5 - ж 4 "2 2 nshshshi pish PI FIELDS OF DUST vya25v36 | 985 | 99559 Yu.B | 7 7 | Ши PY 1717 2IVNA-- 5

Govelyavzv | 8o5 | 73 1. DI oyu 7 ogzvvo | 99 | 9959 | | your fault 22020242 cm o

Table I -- - - -- - - I ------ še I Unocular density loc | en | EC SAME t

Analyzed! anti-IvE 1 Ionic strong | antn-IDE antn-iBE Ionomycin | anti-IDE | Junomitsun | Hut. tick vnti-yivE Ionotrachn ) actn-1rB | anti-IrE antivE anti-1vE compound Tryptase Tryptase HA Hexose. Hexose. Histamine Histamine. Histamine Hexose Hexose. histamine ets4 TME-alpha Pe pozhaeii

Gevit yayu i 25255 -22----2Й2Й--6-62ШВЗКШЗЕК4-852-Ш2-2-6--2ШШ2Ш2202 2 ИЗ-ШШШВШ- (- Ф

WHILE О5Б5--ОШВЗБ-252Ш2ЗШШВ2БВБ-5ЗШВ2ВА--Ш2ШБВГЮШВЩ--Ш2ZIASHNYN towers | 00000111 9999 | 955 | | 999 | 99 | | | ! and

Gunt! 77771721 r i | oya 1 eyu 177717 la 17551500 --

Pr r « t y yy sch vot 00001111 99951 99599 |... 1 9991 99991. shi voi | 00017110 99901 99901001 995 19991110 reve 1202 I 25 "A 5 r o o I t r I 021 I " S. ---51--- so

Gayu | 7771 syu r ryu Z vyaya | || va 771.1 miles 5. 731.1 PODDNNy NOMDNNINvNy

Gwwww! 333171 1010 Ohm 1775 2312 2 PRA 5 L31---

Gdz 00110011 5 | 4 11177 sei 2 2 12 A «A 2 pd TYA --Ж0Й- (Я 5 Ж Ж 2 ( . - « ve 2 OZ 25 S- Z « A R y « R-y-- 5 Y- 5 shi pe dyN Er r 999931... 41. 99.1 9991. 1. |... ho 9999 PA i 1 S OA ZL "Z OA--I 8 svetr tya v rzyu trit" COURSES OF THE NOSE FIELDS NONLONYA MOL KON s 8926113 013 oil | | 995 | 027 | 959 1 065 | yr pUzvya VYS oz yimo 7 | yuyu 0000 99919951 "from | towers | | yah 01171773 107701 4 v " (kom | | 159 - now i i i i i n

Gveit Y010101011771717 17711119 | b They are 10101710

Hm! m0 01 hyu Po 6 I A I YOU t |vyueti 311-479 55 povo 1202 2 2 2 02 5 - 5 - - kazbmo | 0976 199991 F 1 001 95999) 037150 10000110060|3ю0 11

Go | vozbmi | la 19800001 2 11999 | 15 | ho nyny ny i m py p M ev vv SM Ya yyyy yy shi t nt sushi tires SHY CUSTOMS OF MICE Ksh MAO shi write them pa 9999 velo | 07111111... 249. Y 6 1.1 25 -e--- - 2':"x - - (Se) 1) ko 60 65

Table | -

High density sleep sleep sleep sleep Basophil Basophils Basophils vymo vMMe vMMS vymo MMS vVMMoeM sleep Tryptase | Tryptase 1lo4 Hexose Texoi Histamine Histamine Bistamine Hexose Hexose cysts of itsa tre-alpha 1-6 she r «r r Er

NESTY PINNYA PON POV UZN POLONYN. 77 (99th oyu | inininnia PLYNI NOV tower 00000101 999 | 9999 -- 65 6 2И2Z--- vyv 2 (2 5 5 (L Я o рР-- 2 2 9999 9999 -- « tower 00001111 ю 2B-- - 9999 9999 PO POVI KOH square! 5 yu 17707701 11 9951 | ST

LETEtT et SINGULAR PO UN POET UNN NO ttpnvpvpktvatNpnvpnts;u!ya kny PI

Pedan rr (vo, | idf | 6 | Ю щЩ(Х (ГГ | 1718 1 EA--- y IYOTORYAS vh! tt 2252-2502 5-2 "A 6 EU F F 6 F f - - :.:.- 5 - :і: -:5 : 5 :5---- 9999 Mon. -62Й252ЗЩЯЗ-И2ШЗБ6О8В2---52-32-2-6-502ИБ2-ШШ2БШНВНННАНТННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННNN ПХОННННН (| vza | 13 | 4 1 6 щЩ щ | «ШИ! ГГ 2З0101000000770000000000й web | 0275 | 5 | b | (Й | 1/5 1 1 in high BUT in riv ET ---------- ---5-6--525А---ШЙ-55--Ш2БВН-- neza | 09 1 999 | 095 | | 1 Ф ю|' - 2 4-- oeЯ 2 -- 2 ж - - - - ЖЖ « - 2 With --- same comma | 25 | 65 Her Yu Sh Y 55 1 1 1 11 IPOCONNNNNNO OON COCOON KAFKA.

Nst SE t i s g t e kni shi shin ny COMPLIANCE OF FULL NUMBERS OF HNN CONNNNNVI BY THEM,

And vezviai | 9999 | yuyu 011011 WE -- 6:52 - 6 | "-2 | I 2 « ' 6 Zh - same nezezakh | 9999 | 999 | 11117 OD PYKONOKINN NAOP 9999 Vin g tmvpppossoyat oyu;ool lo7ooom-n67i kegvzia | 066 | 999 --ZB5B-B-2B («| ' Ж « ШЖЖ (Я ( 5 А "PO « lo 9999 В т pсСТяятьІ 5999 -- 52 2Б2ИМ ЗА ж 2 2З2З2ВЗ - - 2 5: 35 :3 5:35 - - p NN ch 2 o

Table I

Low density, сме сн сНМо сме сме Basophils Basophils Basophils vm vm vm vm vm vm VMMsM

Analyzed) anti"IAE | Unomycin ) anti-ISH | ayati-IvE | Inomycin | anti-Other | Junomycin | Hut. cliche Tocomycin | anti-IDE | dnty-HER | antichrE anti-IrE compound Liptase Tryptase 14 Hexose. Gehsoz. Cystamin Histamic Histamine Hexose. home | 10 19999 11111111 MON

Beef | 99991.

Ko26387 | 065 9999 bl --

Ks sn skhn nya nya nya nya nya nya nya pnya nysh ShY

Elm6395 | 05 | вбя 01030110 kN НН и ни ни ноя НИ My nia Min Nym nin Nymi pa ach vogvzyu, | 9999.| 9999 | -- тытый SS -ВА---2Н-Й2Н---6Щ6ЙШ--5-- tower | 99 | 955 | Her | (| Her HER M 1 1

From | vyazyug| 9959 | 895 1 sh | B sh (1 MB | write us PO MON Po Oh MON ge) /ko»vao2 | 9999..| 99995 | -- ; ' .1- 6" 262. "6b 6 6 6 5K(6( А 56 -ШШШШШШН---- theory "S. 2 I I O I TT I I I I T I I Т I Т Лта-- - дязвлое | 99599, | 955 1 6 Щ | | / ГГ 1 1 1 17 nolonnh POHONN nezvyoz | za | 999 | km m va v a a o a a p pi a i she t ee 2 2 1-2 --5- 4 5 -5 z - t 926409 Pra K- n ' I ol

Eats 25 1 quiche

Slyaei| вв ШШЗВ-2Ш2ВЗА5/В83- МШЗ--IA- 5 - From the towers" | 05: | 9959 | | M HER (BC 155 Жё ш 10717771 s reeeravo teri rr rt binds | 1275 1 8я 11110001 h | dozvavuya | 99991. 10117177 pi POV NOV NIKY KON

R. 75 SHN--SHVBIA-5SHVYASH ШРВВШШШЗТТУН ЯОЗХЭЯ LU О 2 - « - и и 5 1 56111111 ТЯ o | m 03020177 el 15 vve SHVI 5 6-9 2 A... I I OZ I «I LO ---- 5: :- 52 2-5 2 ---------- 3995 720 POLON mon DINA th " ve mete 1-3 -Ж-ЖЖКАКшА--2.5 2-0 5Ш2.2НЕН--- 52 52Ш ШЧ0-

КозваВИ в ре 2 З (П« | ОН 7 220177 ке ши ЙБ- 5 Ж Ж 6 Е Ж А 6 6 ) «Ж« Я 2 « 6 Ж -2 - и | (I 6 2 6 :( "Ж - 3И-- 9999 Op 7 POLONYNY PON MON KON - se) (4 ko bo b5

Table (

EE reoitlsh sime sNMo snem snem sNMSO | Basophils Basophils Basophils / BMMS vMMo vmmMmo | vmme vmmMmo GT vMmMoM dliyunno) spades | zhen | anti-8E ionic strength anti | ionic strength | House, call

STRINGS NSTU NSS MNY MON sho

Event yav yuyu pra |vei yav z» 77771752525Й-6ШШЗ8ШЩ0ИК8ВШ6668Й2ШШШШШШШ y 2:Й:Ш/ИОЯ 1 I- -----2-2-:33333/3К3- she! height 722ОИЙЙЙ6ШЩБЩБЩВЩЩ--Ш(6?866В 6. 6:ШВЗТЧ0ВЯЯ 6 " Ж ЖХШШ A ЯЭ Е Ж "КИ " - va в-И-- 2 6 0 ОЕЖ Ж Ж (I "6 (I ("I ЯЖ I I "5 ( (I "X ("L"Ll o korenya o -- veni am i o o av Z A.I E I E.S I (SZYYAYA« R' YAL E " I Z Z - 5 5 5 5 - - - I eat her freely 5525ВЙ62ЩЙВЙЩ6ЙВ2ЩЙК Х ХХХХХ)8.Ш85ШНШп 8. -Х)«-«3«3383- vin! la 1 222---2ОШЗВ05-625-52ШВЩЫ--2Ш2ШШШЩШ0ВЩfШБШХХШВ '(-Й0 With is with the same "same 52-66 3- VNA! TV I --- 2shvbi-565555555555555555555555555555555555555555555555555555555555555555555 (6 («'- ee losses of

Vs ts VN PAST: A NNYA POLON PUE BOS NUT UNNYA OO CHAN PNYA VU BEER ZV NAU NNYA POET vima! oz with ZNNNNNNNB6S 6 6Я8Я 5 5,6(х5Ю5ю«« «? ANT

Ivin | svi eya 7z he LYVOIYAYA LO TL RT OZ OEYEYAE " "LZ LN- ee! o» la 1 5 o what la

Galya oz ShVB-5Ш2БВЗ6ШБЩХВЙ- 202ЗB2ЙИБШБШЦС ЗШ PT

SECT s NE NO NN NN Mon Kolya zl -T- 52625 52 И- 2 ШТ 2 .ЙЙ6 z tzhЖ7L- ййн- lхвf(tltl I shen sht i 1 t vi o NN 50 tansy t Port no chn COMMEMORATION OF NOYA NO NNONNKinya mon - 526552 62Й-68-2-Й--

S EANKte now vno no Pa Pol Or svya rano z ry rova vyhv To v" 11 - 522 Sh2l 52 " 5 5 " - S0Z nya NS nya NN NI NNYA NIVY NIZ NS o NGO NOYOU MG NNYA VYSNO NASTYA ver ttt pri.

GEUTETTOY NGU NN NI NYVA --ZZZZZ5B-- 56565656565ю5:5((-« K (З 5 « Ж («(«Б6to ee! shines zi 121 1-21 - 5: ( 5 2 2З 43 (Я24:ЕБщ

Gen yayu oyu 17 -2Ш0-5-52ШВЗБШ-5БШВЗБШ--52ШВ2ЮТНЖХ-2ШВ8БЮЗ8-53555555Й-- -

He a 7 yau 11 yoy--62cpshshshchiivb-Ishiiiiiiii

Gays in Ton --2ШШШ-5Й25БШИЗО2Й022Й2ШШШШШШШВУХСТШЗBONOVZUTUZZZШЗШШЖУХХЧН8Н Z Л 4 t et tr p 2 5 2 2 " "LY 6 "L-I- 65-A4 is " Ж ("« "2 5-5 osa MZHZA--I3Z2B3I358-- ЙКЖВЗ --ЖБ5ЕВ-5ШНШ-2: 3-8 (/ (3 (Й- тВ- - 535 5-353535--535232БББ0ШШШВ82БВ3иЙ3Ш8В3-5- ЗБЗБ-АБ-- : - ж - тЖВ- 5 З 2З «5 ШЩ«ШШЩЩШ "6 060 02 I " " ( (4Ш5-Z- 5 MSHYV--- sch o

Teablich and

Analyzed! antivE | youth | actiiE | anti-vE | onomishyn | antiyaE | Yumomitshchyna | Hut khlishch | anti-ivE | Tonodurkhaly | acts-IvE | anti-Ide | vyti-irzh | anti-IVE compound Tvyptyaz | 1724 | o Hexose | Hexose 1 Systamtn | Histamov | Histamine | Hexose | Gsksoz. | histamine | TSY | EMEzalfa| 16

Gvavvyt vyu i 171TTnSTYA

Gayu tya 1 2 2 2 2 RT IZ2Z2 « «С Ш ЙВШЗ2ШЧ- 0 2И2В 2 Z 5 2 « Ж -2--2-2-И-- so vav | 571 71 1-2 Й-26252Й2ИЗ2Й-62 "АЦИЙ 2 ШШШВ--252--2Ш2З-0-" АН stary nin M-ЗЖШШ-- Ф vymo! al; a ИМЖШШ- -5-5-5- 2 (:З3З38333Б5КБНАSHЗМЗШВ ШВШНШ-

Gvyuei ze 731 - 525 (0 « : : 2 2 - E 225252 Sh2BK«K«KMSHIZVSHNNNT pev A R R L LA--A- 52532 5 5 5 5- - z 122222 12 2 2 A.O | LAA-2 ZR 0 F 2Y5BV- (f (F F F I2Y2ZBK-IZH 52 72 I 1 f ( (-

Geavzhut va with 1 2 L «TL «LZ LV b« ZVVVYA- I « ЭШЩЯ-« gЯЗ6 Ж ж -(6 сх выв ----0-2Б55ИИ5252SHIVVY-И-ИЩЩШЗ60Б--:ШШЩ2ШШИЙ6;9Н 2 С( 1 (YZ (9(IZ« EU OUN Ya t and IY -- 18 Bo

Гевиют рт зе 1722552Й5ИЙИЗШЩВ2БЗТЖИИ-082Ш8ИВЗН5ШЗ8ШИННШН6Н6ИИИШВЦКИННШЦЗЦЗНУАЮУНБуфЦН6Ю щ ПЛ - со во А МВЗЙТЖБЗБВВБЗАЗБ---КШ2КШ2Ш8-- 8926550 9999 - - -5- - - 52 ж 6 ть 3 («З « квовва 19957755 - 2 36-5-5-52И252|ИШШИ .SHISHYSHIA BM (t'NZ kove! 9" o" 17777172 12--220Й-2Ш2ШВБЙ--525-2О02ЙВ5Й-2ШШЯ--2Ш2ШВБВВ--2Ш2ВБ-Ш2В0-20

Гай зв 1 я 17777517225175252-22ЗОЙ2--2-2ШЗЙ-2ШЩШШЗ2ВНТ8-65ШШ2ИЩЩШШШШШШ 2 ИОС«SF - «І g )' | 2-2 2 .-5-25: 7 ee rt o o r "A I I I I E PL I I Tl Lo s voovai 735 --БИБ--555Б5BB-2Н-52Ш2ШК Ж VZA В ББФtФюВх2 Рн o2 ни нзЖ e5 ее tyu Z A LA TT GI-- z» vve! zv | 51 -B5B-E-B5B--552B-BBBBBBYYYYBBZHSHYMSHSHSH (5 5 -z26id; vky pet y р o o ИКЖЗ-А-Ж-Ж-Ж-ЖШВБ8ВВ»8А-- o ВНЖТ-- 6 656Й2Ж « ШВТТЩШЯ.ШШЗТТШШШШШШШШЗИZ6ШУУООШНОШЙУНХОНХОНШТНИЗ 171222020251--252ZVYSH-2-25-ШТЙШХВШ-Ш (2. 25Ш2ШВН98Й86Б (2 Ш ШЗ Я Y : 2-2 -- 5 252 5 55К---- зв Сужеи звола» 1 2 2 2 OO LY A LA L RI-Y--0ШЗ312ШН0Ц2- 50235317

PTS ONEU ZNO NS: FROM PNO POLONNNYA MY UNO OA FIELDS CON MON Mon Con BANN NNYA show R Y "A "R ol

Kt - 2 625 6y: Yahy" - 6 3Й-0-З525З2Г03Ю2КШ2B 5 Э:;С 5 I t ю -6-88 8 Ш2ШЩ Щй ШТЩ2ВЗ A 8 -Ш ЗШ 8 8 5 5 555555З53-3- t -Ш-Ш -Z-Ш-Ш-ШЯВЩЯVA-- 25Ш2ШЯВyB А 2: Ш585-.8-55Ш5ШЗ-8ЗН Ш 22.22 2 Я2 2 --- shk (se) (4 ko 60 65

Table | AND

High-precision I snme I snmo 1 snmeo and snyame | snmso | basophils | Basophils Basophil | VMME HT o vMMe 1 vmme | вМмМо ГТ овММе Т vmmem millet vteve | notes | what titvE | landowners | anti | onomschhnh | Hat sli tire | vtve compound Lriptase | Tryptase ets4 Hexose. Hexose. Histamine Histamine Histamine Hexose Hexose. histamine itsa TME-alpha c-b dose | 835. 1 999 | schi UN PHODYV POONOONNYA OOAKONINONNOM NOOKONO NO NONNYNIKH NNYA NOONOA NOYA FULLY NEW | vegvvgz | 99991 9999 | | оомтппсУО С rezvev: 99591910 -- 5 - ж 5 - 2 2 -б

Vezbeei | oeeyu 09990111 in PO 771 vozhet | b | 59951011 (including | 026 19999011 33.41.1111

Sopezhenyu 1 HER tlAip,огслоги везе 0 бы5 19950000 12200011 дямвяа: ва 19951117 lawsuit g ottrvr;7pr;rt o 2071 ho2bvze | Ii od09 | oh yy r ven y - 2 2 0 "А S - :Щ 5 - Щ ж 6 ( "- OZ polonyn POD МолНВН пишный пр А 926701 2. 9999 OK ve tu --202--52-5ШЗ-З-5БШВБ- Ш-52ШВ-2 Ш2ШВШХВ-2ШВД 0 Ш ( Z (OZAABZBZYKIZ- pev r o POLYN PPO PANOM NIC NNVNNN 063 9599 pov zb | 0018. pt ty r 9999 7 47001771111101lhoo6 | 0717111 1rosoo56 ІІІ 039 | Главхов | soyu омве I K .-- 2 5 5-52 ---- vetyu | osyah | yuyu | 17001110 POVODV

Fresh | 3 | 99991011 (vet: | lab | 09999 | | s pavftyur tr rr 2 A PR r o i 14 PYDNONNN POLON NONn Mooninn NAV mon - 4 ЯЯ б - 892675 UNO PROTECTION MON S-- 5 deputy | vv | KB | tt g -- ----- 3 vyaze 12223170. MON SAW urine

Table I Sho Ge)

High speed, y snme fo snMo syam | snme | sims | Basophils Basophils Basophils GOVMMS TO vMMs To vmmo oi vMMe t ovMMo 1 vMmeM compound | Tryptase | Tryptase Msd Hexose Hexose. Histamine | Histamine | Histamine Hexose Hexose. histamine Ile4 TME-alpha I- vela olen o OVES 1 A- 20100011 i p 926773 | 2891 p b (vase | 3055 | 8595 | 01111101 1771770 take it | see | z | 001.01 01.3 3313... take it | 9599 | 995 | 11011110 or fir tree we nm vn m v nyan nya nya pi pi Man hib 20207177 scha veto | 02 9999 ------- 5 5 43 2 00431010 zhozvtsia | ag | zyu5 10100004 00100001 0059 9999 77017217 717777777770 00511100 0817

KVU | byu | 999 11111 А- ю т6Я 6Т 5 5 Я Я хНЯЯ (kab | ay 199991 st ---- t t v z | ok26741 | 29085 | 9999 | 11 | z | 0.537 s sa 1 | 1 o043 | ve | 0055 | both | 1 005! blo 0053 vyt yayu 2122 2 2 LA LA « LA-SHVSH8VZ-5-- .

R. yasnykh nynyn nav vn nya p o nina p po p p Ma p veli e-- in 5 "( " I 6 b 2 6 A -- 352 :---2 --42 ----12-- 207 -071 1 pnia Gender UVO POLONYNY PONOONVNNYN UN TONS BY ZONE COOOONVONYA PANNO 04 | 99595 | | 221101 712707 POVI PI ovi r nstnyakhotyamtppppnnatyazhpppa so vit at at --5B52--5ISHBVSHA-A- -20ZBA5 5 Ш2 52 5 ШЧААЗАЗАЗАШВАШВАБ -- ven uyu rose 5 A 5 2 A 25 2 Zh 2 - - 2 - 2 pi 22007 p. with Keo6t65 489 pi Pn PON PODYH POLONYN oIOONOn ZV shk (se) (42. io) bo b5

Table

Visokatilnet snMSs sn SMS sms sne Basophils Basophils Basophils. vymo vMMo MMC vVMMs vMMsM

Analyzed anti-IVb | 1 Ionokeatsna anti ryantya IB | Unemicin | antirE | Iunomycin | House mite | zyti-ivE iznomycin o | anti-ErE | anti-IvE anti-idE. anti-IRE in reumervt slot and AT NN zhatet and oz 170717 МЖЖ- « 5 Ш62Ь Ш 2 Р 5 Ш ШШШ (Я ЗР « (Z (Ш « « ( Ш ( (« Ш (« « ю Ю О« « О Z doct HNN PYSHY PANNA NONNNYA NN -0IV8- OO 5-0 er МШЗ- 525252Б2ШВ-ШБШБШШШЩШЩВШШ-

Gdevta Troy 1 tat ШЖШ8-- 52 51 '« Shzh | Ж Sl lo uter vetrtet tt t 2 RA 252 5 5 "2 5 5 (Z "f" ЮЕА- ИЮЗ2Л626?3б5б Ok Z? b kozhtia 1934 | 7935 | y y yy 70 МЖ- 2 5 2-Ш-Ш-2 -SHVZHGBSHVKURK SHITSH ASHCHAD- SHSHZHHI VC y) - - -« 55 -- neztyu | ovi | 9999 | B- LYA | I (I 5 |. ---- 2 I I I I 5 I I I t lo

Guyent and oz 00200 иЙ3--ЙБ52252352052ШШШШШ 177

Гежвлют опа т я И-2ИШБ2БШВЙ-ШЩШЗБЙВБЙИЯШЧА-Й2НШВБИЗ2ИЙБШШ2ЗБЗШЙБ2ШЗИЗШЗШЗШШШ0Ш ee et r R - 5 565 А А Я тя ож | I work - 2 5: TSH00 --- реINE En and nn EE, 0304 ho 1741. 1

Ivan sa i 17771772 т8Й3----5----- p-e8--

PESEN PISK UCHI NVETCHNNYA NAMA PON PON VANYA, ON TEZNY PNYA KOOGSUTNNY VNKUT NN NYA yati om | of 17777771 7711 МЖЗЖЗБШБЗАЙПЗИА-А- 5 У 1 « I mitr I8Z5-- 5 5 5 : 55 5 5 2525- giant Р A T-6 262 « « I Ь«Ь LO ОЬ «LO | R.---2--2-2522-53-5----555ИИ555- 7И5-52525-

Gdevvyus pay 1 ty 11 25IZV2Й5Й252Й2ЗШЩЙВБЩЙЙШЩЙЩБЩШЗВО6ШЙ(0ВШШШВВ55 2 2З6 «Л«Л«ЛюйИННШННШУЮМНИОЗЗУЗЮЯ

Geaeei v 17 26727771 vd toi noi b lo go rshei et trt 2 2 2 2 А-Й-5-52525--555252--52---552--5523--55--52--

Gkaeth her for i -525- AR RO 5 L LA «A LZR LOTTO

ENN MON NNNY NONONNNNNNNNY POONONNNNYA IT KONONKO NNYA -535555525-55B5- towers Ta I-Ж--52З852525 2 6 Ж -Й - t вх» | zv | ве 17777 1771701020500150 МЗЖЖ-- 52525 2 5 5 2 Ж-З2В-2- Я 6- ko26795 2.347 5.87. З58Б58Б0- НИ КН еютт ше п -ОШЙБ50-ШЦЩЧ0ЦО- 7Й37З2- - --

POET OVY NNERESTNY NS SNY PLOV PLAN KLON NOV KN IMZ-NN-ZHSHBSHVCHKUIUVYIIIII5Z- shch -- "Table | o

High density snMo snMS sms snMs snMo Basophils Basophiln. Basophiln in the VMS is called VMO vVMUSM compound Tryptase | Tryptase yts4 Hexose. Texoz. Histamine Histamine Histamine Hexose Hexose zistamine and TIM -vlfa p. 17521722 2З22ШБ-2-2520Ш05З3-2Ш2ШБ0Ш2ЗБ-- ШЖШШЗ-0В280-- «с зх вы 1 зю 17222222 22225-2202525---220ШЙ--Ш-0-5 МЖШШ-252525325-7 зо (1 25 LZ 2 17 MZ--- shi 0-7

МШ8-К5ШЙ2Й5--1- -Й8-- 0Й5- И-Й38- Ф

МЖЗМЗВ-ШБВБВВ- 5-8-6-538-32Ш5Ш2ШШХН203- МИВЗ-О-- 5-5 5 5523253335032И3535353-

ЮМЖТШВ---ОЖ56-20ШЗШВЩЩ-Ш-2Й Ш ВЗ ЖЖАШ 2 Ш Я« (|Ш "Я «З Z yuyaЖ (| Я ZITKNNN-IZ5- same so I 17717 ШБЙ-Ш2Б2БШЯTVВШБЮ8ИЗУХЦХНШХХХХШНШНШХХХХХХХХХХХХХХХХХХХНШНХХХХХХХХХХХ - I ЖЗО- - seni zast o 2 A RA Ж Ж I I I ( Yah 5 5 5 56 ( ("( I (Ж Ж (I I « Z

Glyv aatty yae11- МШЗШВ--И-2ШЯ3ЗВ38ИБ-5525БШВЯА 2 VZA i A 9ЬrlДl -- cm

Gezvy 1 same 11 -8Z-5-Z-Z-55-5255-52BBABZBZBSHBBZBABBSHMZABZVABSHBVZSHVSHZ»b animal right 1 MZ- l«2-Ж- 6 Z « :( ( (6Я8 I Z R 5 (Я« I « ' « ЮХЛЛОЯЗ so tin art МЖЗ-Б236Й-5--2БЙ--Й5Й2Й2ВЗИЗ-6Ш56ШВЙВЙЙШШШШХОЙОТ З--252525 5 95 ( 2 o vat va ---5-252Й2Й-5-5-5-5-20Й ШЙ КНИНК- IZV-O

ЮМШ-ХЩВ-52БИ-2ШШВЖ-Ш22ШШШБШВШХЮЩА8ШЗ Ш Ш2 Ш 2 :ЖЯАЕ 5ХхК 6 6 5 52:5.42 -0 : : 2 :::.:40353-53270-3-

Hawaii | осв 195957 ЮМЗЖ- 5 ж -О-Ш 60 6(« Ж ()йЖ (Л ЗЕЗ З б (-- И3- МЗ-- 0Й- т-0Й35- М-Т-- 2Й53--20ЙВ83--О- 999 9999

Ptn SLYNY: NN NNYA LOWER MON Noya polon SHANY M-Wh--5-5---- s ONY NN TYNY NNYA NNYA FIELDS FIELDS PNYA PPO No oo mon mon ZAV 8935016 9999 i- "z vet -ШБ--5- -2ШВ-52ШВЗАШШЩНВУКНННВАЩННННЙ о пев яв МЖЖ-КИВЩ886.2Й252Б ШВШШЗВТЗУК :Н 6 ЙК( З2Х- (Yaya« (45-03: in the evening 1599 ИШ5Б-- 0Й3Й383- МШВ--ЙМБЯ-- 5 52ШВЕ2Й82ВИЗ5-2БИЗ " ххх Ho

B latr i 171772 ----52------- МШВЮХЗЗ-ЖЖ-ЖЖЖВБЖШБ6--53- blade 8377 5 write stump according to M-- И5-

Ivez5075.1 093. | 9999111 r y - so Fri: NASK NN sny NI Mon to mon noya zi МЖЗБ-ШВВ-ШЗБЗ2-25Ш2 Ш2Й2ШЗН--Ш2Ш2-2Йий6Ш2ШВШЗБ0Ш60ОШ-6-О0ШШЩШ898 t POSTEETTECHI NOU FS SNY NNNOANINONNYA KOOLNONONNYA KOOLNONOLNYA NNNO KANO ННО ННО ННО ННО ННО ННО ННО ННО ННО ННО ННО ННО ННО ННО ННО ННО ННО ННО ННО ННО ННО ННВИ (se) (4 ko 60 65

Table!

EE High density art

Analyzed anti-IVB | Ionomishny | took off antn-IBE | Junomycin | antennas-IDE | Ionomycin Hut. tick | vnty-IvE Ionomycin | anti-IShb | anti-IvE anti-IvE anti-IvE compound Triltase Tryptase ts Hexose. Hexose, Histamine Histamine Histamine Hexose Hexose, histamine ILSYA TME-apifa Poe

Huh? | yayu 71017007 so tt pop | keziz4 | 0909 | 1799 | И-- 6 (« 4-5 Ж 5 2 ж2 (Я '.:'- Щ ж - 46 5 Ж - - А - - - и 6 5" 2 - --- - -- vozi | de | 329 | . t'5 - - reve ele in Z 5 4 6 65 F 2 F :-:-55-5:------3---2- 5 - 5 535 -5:535-- vza | 26170001 111 1 1 1 1 1 70 Pigs ov 1 oz 22 (2 L Z LYA 5 (- F« 5-5 - 5 f F f f 5 I 2 I L I LN--- (vimo 083 | 99 | |. 0 1... |

Sewing machine with 2 32 Ch- F f 5 f : - A -- 52 5-55 5 o 5 Go t 22010021

Suvvme | vav Groza 2 (SO L L - 5 - 5 5 I I I I Ot

Sower, fall 1 s2yu Z 2 Z L I -- «59 '54L--- Yae - 5:35 :-:----- - y - - Ot vozziyu | I" | la | | Kk | tppNtsstshpog 77-77

Sveevi ovev 10 25----0------ 5316 S-- I 5 :5- 2 5 5 KBA- A poh NANNYA baker 5 PON OON KOVO NEWS KOKON VYKON, mon 921 go shi pom 1111111 oo 15 | bi ІІ oo odoi 5599 t Yatyuts/tsh.1

And wash your feet 20 | 330.1 ..yuЮЩ 21.30 Щ| 1.6shD M | -- KB "Z Ma 1 22 1 2 5ya -- "-4- 6' Ж I 6 I 2 6 : -- :- 5 -- --- -- in 2o | nau oz | mo 0001111 sod ryavmnyu Va 15 - RT 5 L-- - 5 « o ha |. 1 mark, | ov

Mon.

PDK ONY NOM, -- и Я AZ TB ХХ ЯХ Я Я кезиве | oz | in 0 | | | | Mon Novo Polya Nina GT sech 25 ----- I - - « -- « «

Table | o snys sne simMe snms sime Basophils | Basophils Basophils vMMs vMMs vMmMmo oi vMMo vmMmo TT amMoM

Anodized anti-IDE | Ionically strong | znty-irE; anti-Leb | iohomishny | znti-ivE | Yunotrakhn | Hat. cliche | anti-IDE | Monodrachn | anti-irE | anti-ZvE | anti4fb | vnty-ieE demiya | 3.52 1 50617011 10001101 voi 10011700 TT write us p 30 breaks I ol yr 6 5 UR O LN-N-- | "Y A , 5 same '"'| F 5 (2) euros PY PY MON visit | sia | 0 | 15 (1 55ФЩ1 щЩ5Щ15 5 .ЩЙ 521 1 1 1 1 "- vase | а 1 99910010 01310410. 13.3 1 1 1

Gvezitya | ov 19th 10111111

Gtit | adve 19 А---5535--5Й---5Й-ШЗППО ОО 2 o si

VNA--- 5 5 3 02012000 177 cans | ovi 1999 HER | 12

Zola ov 99101100 102120Ш0Ш00020200Ш0З5003000050Ш23010Ш0Ш02030Ш0Ш20207510003533 so

Xia | in 00010111 07110007 ber --- veins - 6-5 (L S - - chЖ 2 - -- 1 --Я 6 -Я! shi ovo І111011000110171771.1777 PD, suviet 2 5 Щ ж 6:52 5 - 5 ж 5 62 2 2 Ж 2 2 2 - :- 52 - :.5: 5-2 535 ::-5-F----- « 8933186 9999 NYMY MON FULL POOOONNH UNO MON PODA KOKO END OKO: NOOKNNNN 40 ec! C 5 I I I I L LZ z

VEHICLES 5599 sets 2 3 І І І І І І С І ССС І І І І s Dreams | oviyu 999 | | |. K | GG ptts st kino shi shishishshshishshshshsh shshsh shshi shi shi shshsh shi V V h SYA ovi yuyu 01071101 GO oo81.. | soy | ogiz | hundred | oh "» rya | oz; 1 juyu 11101111 0771171

That's it oz 1999 111111711101111310101010131731001411 1006... 1 ohm | lake" | 009 1 0037

Sk) by) z» 70771711 tt» 11 vom du | ome | om lit 70732Vit r 45 watts И- p0Й7Й35Ие2-5З3 pnia pn so pev meti ze 2-0 ISHSHTBTOIMUY-- 5 5 2 5 2 523 vini shi 8535195 045 ho shi 2

NN kz nu and g p MY POLYN shk (se) 0 ko 60 bo

Y Sho Table ee EE ke snMs sn sny snMe snMs Basophil Basophil Basophiln vymo vMMS vVMMS vVMMS vVMMSs vMmMoM

Analyzed anti-other | Nomicin | nteIdE | antiChya8E | nomicene | anti-MORE | Youth Hut cliche | viti-IE | Ionomishnn | anti-IvE | vntn-iSHE | antichdE | actn-yivE i ree Org put orto tb ze yayu 1777712 2 2 2 12 A LO LZ LA LO 2 5 МШЖШВЖЗНННБВБ- 5 Т-З5-т ee yur rt р р Р РА 2 5Б-ШБ 5

Gkviziu TT ShBV--- M- 6-6 ""I6OVO-533-52-- 05- ee humor zv 177377 Y- SHIK 5 Zh 5 ( Zh -62Zh«IZZh z 5 5 5 543 I 6 C- 2 (I 935 5 | (-5e2Я- 0Й3-

Hnat oyu ov 1 1---- MVZh- 62 (ф("Ч" (Й -6- ( Ш фШВ2--ШЙВБХВЩХВ--5-355---

Giyat tloyai zv 17221722 1-3 ИШЙ-2ЗХ 2 2 ЯЗ6 202-662 ЖЗ-З-З2020 О2З 5 ( (35З-5 Ж 6 ;( ( -Й-- pet r rr r 12 РА A О5--О20 ю Eevvivtttv t t rr o o 2 NK -3

Gazy oi ze 177221 2 Р ЗА ЛЯ Т ОО т ШЯ Я Я ЕЯЯ Л LY /"AEKBMZMBASHZV- all р р р 2 A OO 25 Z vamiv t zyayu 1 yayu 1771 I-T- 235 32 5-5 6 З2VAIZSH28BO -- 2 2ШВЗХИ-2ШЗ0ЮУН8-32-Й532Й-- яоухмю | downpour | 5999 | р-н 0 5: ТЛЯ Я Я t Ta t я»Yaya» 65 2 ж - -я вела рою yyyyy 5 M--5-- Г0Й-- kvayuvo | jan zv 1771 --BBB--5B5Н--- MB-- vvyuye T ze z 17777771 1 -- МЖЗ-- З .О« | ЖЖ ЗК ЖЖ 6 yunnoy tee 17771 -- 65 0 523 525252: BREAKDOWN SHKNA-Ш2ЗШЗуT

ДН set всуся t НОЯ НОЯ НОЯ POV UNO POLON VN Pon VONO vy tot ty 71 20-2ШШЩ-2-2ШЗБВЗЙЙ5-02ЙИЗЙБЙБЩИВЩШШШШ2ШВИКИЙЙЙЙЙ -252ЩШ- 52 5 k 6Ж- vet yav rt r o r 2 RA 5 yayu ya Is it 6? Я (ЯЗ2 5 5 - - к kmshe To 71720177 МЖШЖЖ-Й-5-5-5- 5 (Ж -БШ-2Ш282-6-- МЗ- 5352 «« И R Ж «( 6 (Е -б 6 -5б Ж - юю 2 С 2 А 5 RTAA---- 2-5 2 Ж 5 « ж Z (6 (

PvyuvY 711 IVZVZ-2- 5 « « Ж ( ж ЖЗБЖБЩ8К-- 2 2:25253-5550252ЗИ-А5И5З5З32ИН--- - I EI ENN NN kogog54 | bob MY 940255 1033 9999 ---

Hvmet zvav 1777771 2 1 J- 2 (t t083-- emo! oyu 1 i 1 2 LO 2 "ЛШВ--2252Ш2Б0--Ш2ШЗО60--535-533-- -- yuyu i zha 121222 02--2ОЙ-65252ШЩЩВЗИИ --2ЩЩ6ШВЩХЙ 2 2 2ШЗ2ВЯА- SON I Ye kish yayu i 177 1 2 2 LO -2 2 2 NTKNYZH TL OY RT 62 2 « « («Щ I I «b 6 6-Р « K -

Iva z z" 17777177 TVB- "6ХЬ6-ШЯА6 6 'НШТХ- 6 "(( "6 Ф6Б5635-- -- сч в

Table 1 about high-density TE

Analyzed! Antiezh | youth anti-ISHE | antiivE | vom | antiiyaE | young men | Hut wedge | anti/pE | Ionomynian | anti-IvE | anyati-IvE | anti-IvE | anti-ieE compound | Tritase | Trintase (tov.

NO NIS t NO NO NIVI MON POLON NANNYA FULL POLON COLONY FULL COLONELATION MON, KOKON on en yuttia r 2 A Z LA - Е ОН o «s

Hak ba 1711 PON NNYA PON NO NN PONYNI MONA NIZHNYU NGU NNYA with peyrutret 1225 F ve ty --ООШБ-52ШВЗВ--52ШО0ВО0-ШВНН- 2 -92Е62 6 «o(yu 4 l /LD- «9 she I-- century -

Hek syu i 2 2 12 "LO L-Ш2Ш2И2Ш262ШШШВЯАШЩ0ШШЩВБКВШШШ2Ш-ШШЯ З З-З LV R 2RLt РИ РЖ Z ИРВВ6б5 I o

Gyunt si | I 177717 1-ШШЗШШШБЙШШШЗШШЗБЗБШВЖШШБББШББШБШ8БВ9ИКЗКЗАЗШВБЗБ8БЗЗШШШВ2ЗЗШШК3--- -503-

WRITE IN PISTYNNYA NS: li NNYA IAZU A ЖЖ Z А-А IT -А-- 1 5 :.5 :1 5 1: 1 5 o SOJU To sch

Goa To ve 17 MZA-ShZ-- 1 A ro5 "1 Z ov t oloy z vee vy 1777 MVZH- -N ЙЙ НН т ТЙ 6 0 Щ3 Х " ("6 "Я б" 5 1 З" "Р t so etheri 2 212 o o 1 2 5 Z OO vav, oyu in 17 e----253-II-2SHBY YUR ShZOSHZ tota r t r 2 2 r lo

Hacknet set! зи 77252172 2 2 5 0ZLATOSH25--- - 0- ШШШ--08-- taye oz 1 ze 7 1 2 З « 1 1 Лл l - ШХВЗ-А--3 И-0-- « tva | зо» Б-Б-Т-Ж-ШШ-В--252 -« - - I 6 6 6 5 | |With 555K3KN-

Gay people -2ШБИ--ШВЗБКА--ШВЗА-Ш8ЗВ-52ВЗ2ЗШМШЩКННШКБ 2

Gbaogbo | words | 9995. | Wed 55 - 6 55-34 | 059 | 0246 s vav t V---ShVN-I52V2ShNNNIISHVZVTN--NONN --- - - ovo I-73 "from Set I---5:5-I2IVIYYZ6-6Й252ShVZOYUTOINYY::ShVShNVA NK Ts 0P1« EV 6 --e5

Huhia Zieta you 2 2 2 2 2 2 2 2 2 2 2 «Rkum-Bshchvmkshshshshshzhthostshzh seams And from the nod-8940297 1 | INNY UN NIOOVNNnn kOKHOON HO sogN PINNNNNNYA - - - - (5 1 - - write pinn so sect tia ООО05- -- ЖЗТВТ-ТИБТТ-Ш--ШБИБВБВ5ШНИ35Ш53-

SEUESEENI NSTU ON NIYA - -3 p-0- iY--K-- t konom! МЗ--Ж-5-5- 0 Ш6 От Й8---- МВ-- ko 945035 9999 shi g NT shk (se) p ko 60 65 -2wt-

Table shk Low density High density sno snMso | Basophil | Basophils Basophils in MmmMo | vVMMo vymo

Analyzed anti-IDE | Minotarachn | anta-rE | antiirE | Ionomycin anti-irE | Ionomycin House mite | antivE | Tonotrakhn | anti-IuE | antk-IdYa | anti-i8b | anti-IvE compound Tryptase Tryptase 174 Hexose. Hexose. Histamine Histamine Histamine Hexose Hexose. histamine Its4 TME-alpha pev vegzosie | 99 | 999 | 7 7 | popovvpvvsts/ osi1777220711226262202l opostvat 56501 2 Z I 9 S I TT I TIA TL LLYAYA YAN --- voakhoz | 9599 | 999 | :: | (B | Щ |. Щ Ш (1 . 1|5Ї56Ж5.ЖЩЖЮ|55. D y 71777 keazog | 9999, | 9999 Wholesale o 770 veya5omi | 9999 9599 ts MON MON 9999 EBA- 45 6 5- rt yy yy 9999 i - - --- MUST WHILE koyazoeh | 9999 | 95 00001111 VZA- 5 ж 2 (4 (Ж - 2Я|. I | I -zh ' t ---- vzaae | ba | 2yu | 10710101011 111 111 1 1 On 70 yr Sen ovo 5 X--4 PV FRI MON FIELD MON NOV z 171717170310000070paйt7ЮуТвС,ОТ ве пере M --252Й5----2525---52-5-55Б5Б5- -85В--2BB-5Й5 5999 con zh g O1pSoopd PON ONA. ee in o -5- 9999 ЙБ- Я | 5 -4- 5 - ж 2 rn sSvezhe ev 1 25 2 T--2- 65 LYA LAN 2220204 p ke 01855 10561000 shi ooo vzyazovye | 053 | tyu | Her DSH F/ yy r 2 2 - I yy POKONYVNO POLONYNY POLON PN s--YAYU- I vue | 52 | cho 0222! --

Sevmi vv oi v O I B« I 5 "TYA t tTtT LIA I YAN--- POLON POLON i 77041117 1 sot yayu (7777177 POVI VYN NN PI voa50yu S 177 r

EE na zhana zhan a ana 45109 perriettt ny shi pd 107 77017177 shi PY oyuev | 9999 Poppatt

Vo45iza tya5 PIONYINNH PIKYNN SUBMISSION JOINING SO FAR SO FAR s nn ia a A o eV o nn VE OT High-amplitude snMSs sim SMS snme snMs Basophils Basophils Basophiln. vMMs vymo MM vmMmMs vymo vMMoeM of the wound and | youth | age | anti E Isnomifna. anti-IBE | Gonomics | Hut. mite actn-1vE anti-ivE compound Tryptase Triichtase cs Hexose Hexose. Histamine Histamine Histamic Hexose Hexose histamine Imkesi TME-alpha 6 veazyuzh | ov | ho | 00011101 kaz | 99991 959 | 11010133. ke: ba 1 85 11011111 re) ven ron Go 2 ("L LIA l LIA Ye Е TO I I I I OЙ t L TtTt I I Sl L O YEN OIA I I ZIA b« I vzaloya | 1003 | 20 | Щ ! | 7 mon r-n 6 OO (e") legs | 0701995 000010 -- 2ЖЩ«!І 4 Ж б 2 6(Я A « '«- ж ' - - - - - -

SEP Kerr rt IPOCONNNNN POKNNVNNYNYA POKNNONONNNNYA NONONNNN NN COKON h- vozizz | oh | 2060 03110700 toch 7y/y- 02 2 L p 0 l ta0НtТtllss;й/ЯЯЯ voziza | 9999, | 9959 | (BM| | 1 5-55ШЖ15 175 1 717 7 7 7 7 Ha veamzh | beats | vm | 0 |7771710171717110101.1030 1 IT PYNNNNNNNNONNNNO NO NONNONNNNNNKNYA NNOONNNx NOANNN NN,

Cheese COMPLETELY FULLY WHILE NEWS NAKOKVMK THEIR BEERS.

From 000 | veins io8 | vlya | 0000011. 7. so svv ne 226 2 5 (A-- «y I (I 2 2 - - -- 1 - 5 :5:- 5 :5-- 12 A 5 tyu ---- 5 92 A 5 | pt

It's kovyaivya | | region | And 9999 | YOU WANT THEM ---- 69 -6b6 --

VozUme | 156 as now and y Pi NN nie « dream book nya no pi You t ooyoyuttgtgnyich (veze odot | 9999 | | na nov p po i po pa py p MY z poz mo euro rr Opt s poazizo | yati | mo | ...| worship of the gods Ha | YuKuYi1lo2a 0 1ooyuyu | oyu | om vera 2 ve 5 (RA--- 52 I Z5 « «5 - 5525 - -:- 26 - :-- 5-52 5: 5 5 5 ( |(-6 - 5 («РрнШ ШШшВ. "» show up i nn p m i p VO rr i READY MON NOW MON TOPOK POKACONY NI NOOKANNNNN ol --ya - - 5 ---- -ya - -------315- - - CURRENT FLOORS ------4---- PV MON WOLVES KOKVN | neame»: | 9999 | 999 1. D yu YubYMmKYi«i p po po p pi av 7 7

Go! million I in ny niv py ra MN pi pi p yu | I am | Щ и 5Bsh Ш B| and NNYA BEER 7 5959 | 999 | | CC | POKNONNNNNO PYOLYNNNNNOYA MON COKON FULL shi ko 9999 55 1 11 HIDNO MUST TINY POKOLNVNNNNYA PNO NN PI -y (Se) (42) ko bo b5

Table 1 of them

Analyzed anti-ishE | Ionomishin | antiCheE | anti-eb | Junominny | anti-EEEE | young and strong | House tick | flowers | Zomomyshchyn | anti-aE | anti-ivB C) antilet | anti-idb compound Tryptase Tryptase tu Hexose. Hexose. Histamine Histamine Histamine THexose Hexose histamine 14 TME alpha 1-6 century | salt 17 yuyu 17 IP 5 fiat ve -5--52000--5ИИ2ИШБ2И-И-- -- ИШЗШШШШВ350--0-0-

Geteti yu 1 5 12231225 0-6 IMShZ-T-SHII---- vela ze 212 2 o ИИ05- ka | with! of 17

Puaikht zaya Tyuyu 17222171 5105-02-57 MSHMZMBZKK(UuUYUZZ 2I2 2 3 22 K « ll honor nin bat I yayu 17220110 Х- ( (Ж Х 6Х«-5 2 6 ('«ЕЯ 2 2 (ЯЗ Э 2 --

ME TETEENO MOGUT NN TZN MOVIV POLON POLON NOONONONYA KOVO KONYA NOLnLnNNy 5 IA--5355-0521275--

Owls: zve o 1 PNA-Zh 5 5; 5 Ж I yes ЯЯ «« - 6 - 70 ve 17 И--202Ш2Ш05-ШЩЗБ2ЗШШШБЩ0ИЙЙ-0ШШШШШВШШШШЙБШХVA--2И2Ш2ШШШЩВОЙ-Ш62Ш2ВЯ-ШШЗB20Ш0ШШШШВБШЩШ0Ш2ЗТ-3 with coffee | 59551 595 ЙБББ3Б8Й-Ж6--0ШБШБ5Б---Ш5ШШБЙ-ШШ2Ш2Ш0Й--0О07 tSHIVZ-ЖБ-Ш-ЖВБЙУЖШЩХВ-Ш5ШВ2БЙ-5Й5Й3-0ШШ2Ш282В2VYSHNO-O-7 peck nik ny ny VYM Pi vin nan i In vati p vin vishno with З 5 12 5 2 2 2 ор возом 1 ож 13557 ---ЙЙ-Я - Ж - - Ж- 3 : I I R rt 0Й3ЗВ3В3Й5Й5- МКЖВХШШШШВШЧА:?.:.ШШХШЗЦСУИЗ Й 626 656 « ( «lLRЖ- «Р « t Write with luck? Ж ( (Ж "ЖЖ t (Ж" ( 5 ЖЗ ("Ж ("Щ 2 (LshL Z

ШШШБ-ШЙБ35БЩЩ0ЙБ-15--3 ИМВШТБ-- -25-2Ш2ШШЗЫ3А1ШВК--ШЗШШЩЩ Ш л отзЛ

Goa | 305 17771110 -Z-ЖЖЙ- 565 юЩЮ (Ж Ш(Я Ш " TR kohoigya 135 ОО ИШМВЗШЗШЗБШБТИБЙБ--3 ИМШЗШ--5-535-- kovo 11575 write t555Б050-8-22ШШЗИВБЖ8М-025202SHIVBK-2-З22ШЗ-Ш0ШШ01 -0- is fighting 1725 О00ШЗШШШЯЗШШШЗШЗ0ИЙ- ШШЗМ-ШШШШШШБ-ШЗБ0ШШШШШ8ВЗ-2--

It is in 950130. | Series

Gyazyuri 1 97177 pt tr t t TT "RUUuSHISHYVI- 2 " RA t

Pevei, with 2 2 5 R--25-2-2 52 5 5 « ж ж ю -Ж ("З 6 "(Ж Ж Ж Х Ж "Ж Ж "( "Ж "5 6 - 5 5 ж

Gweiui 3а7717 я 11- 7053533 0ИВБЗ--SHIVBY---20-2ИВ0И-022-2 2022-22 -ОИЗ52-2-2ИЙ-0202-2ШЗ5-О-

Gvzhim her body | 51772721 иЙВЙБ-ШБ-5Й- 25-22 pinyny nin novo 03571772 1 polyny Mann МИ ЮШЩШШШ0О05050ОО-ОО0-52З vvrettet R LL I TA S TL O SL «LIA LT 6 I I ol i pesstetnystv nin tlNN- -07II352- ! 7 c now a a a

Table | Go)

High density of smMs smMse sms smMe snmoe Basophils Basophils Basophils vim vim vmmio Navy vVMme vMmysM

Analyzed! anchti-vE | Мюномишено| ansirE yanti-ivE | Ionotropic | antn-M0E | Iomominny | Hut cliche | acts-IrE Tonomycein | acts-TrE | anti-BE anti-TaE anti-IvE compound Tryptase | Tryptase and Hexose, Hexose. Histamine Histamine Histamic Hexose Hexose. testamine ts TME-alpha 1-6 watts! Sun 1 Oi 17 PISHNYKH MON Nonna Mon WRITE IRRIGATION UNO NOV Fri A R 2 R LTA--Y- - z 5 5 «se

ИЗТ--8-658-252Й5Й-2052ИЗЙО2Ш2ШВШШЗШШВБВЩВ--ШЗШ2Ш28ВЗVШШВ8ВЩШШШЦSUVO ТМИЗВШЗШЗШ0805Й-

Gezhaye | ю -И- Н« ( 6 PA 1 5 - О05-

ИМШ--2- 5 35 - --і3 Ш-ИШОШ030- И05И03- Hey!

Guyumt| 17771710 І-і-- 5 69 9 9 I жШХЯ « « Ж (5 (t Ж; 3 (82 5 -v. - kova | | 275 иК ГГ 99 | OVODINN NOLYONINN POM NOHONNNNNNN BUT PO ONY BURIAL OF NIKA -A- lat Р R 2 A ХП б o

GEETTETNY NNYA NK UNN POLVNNNNYA CAPTURE COLUMN HORSE COLUMN ONE MON COCONN KONNOLNNNYA ONY KOONNNNN kN si vozoya: | 9999 rt rn t r 12 I | Ya r i Ya ev pet 2525-25 M-- « 5 ' 5 yu32-5- 2 - so

AI --

PETYA SHETNYN tv Prnya voya ---5-52025- t0Й3535- МШЗА---3 vav r» -ИЖЖЖЗЗ- 5 555Б5БЖХ- 2 2 54 . A RT ххК MYBBSHSHSHSHSOBB-

Ikva Tvvov polyn PN POLON NNYA ШЖ- 3 56 532 щ5 55 25 5 1" (liu 3 Т0Й5Б535-

К950158 ПОКОННННХ КОМКИКНИ НИКИ ШИН ПОХН « ев заст t 2 21 2 2 2 2 о ИЖХТЖ--50Й55-5--52Й--520Ш205-5Ш0Ш20Ш000

GE TRU U PNO NAVY AND PLOV NOYA PON IK- 3 5 "5 6 5 (Я f Y t ( F (ШШШ 1 L "L ( Z

Gee! we. 1 зю 1725152 525---22-025---202ЩШШ--0-2ШЗШЩЙМШШШВЗ-ШШШВКШЧА-ШШу AND ВЗА ЗВЗЗЗ-ЗЗШЗШШШ-02ШЗ3Щ0303503- -о

Ko50163 ze 101 shi shi PO POV PON 4 s povotya pev 5 2 Р р kozotyeh | tovy | 09909 А- 2 2 5 |- 5 - Ж --Й2--- 23-- :-4 - I 1777 "with fighting ya! I 17777217 2222512Ш21-ШШ0525 ШХЗТ- 5 5 2 ВР-7 кезот68 | 6496 | 8653 | | | ОНОИНИННННННННННЙ НИКИ ПОКИ 1 4 я5 ev» 1 2 - o - 5 0IZ5-- io MA- KZ 4 5 ISHVB-0-- -IZ5-- so i 17122222 write pi NLNYA i7I5-i voi | yav 1 zi 1 - 65

Table 1 What

ME che High density is analyzed anti-IVbB | Ionomycin and antiv antn-ivE ionomycin | anti-IvB | Ionomycin r Khat. tick antn-idE Tyunotrachn o anti? | anti-IVE. anti-VE anti- 1 compound. Tryptase Tryptase Is Hexose, Hexose, Histamine Histamine. Histamine THexose Hexose, cystamia and LTME-alpha more

Sweenle ia uovya 2 2 O2 PARADISE. 5 5 « 525 24 «25 625 6 - f 5 - - 5-2К( 25 2 ( 5 (- 5 --f - kit | zvi 1 zam 13333317 IISHTTSHIVZY-0-О-ОИИЗШЩ0ИО- «ТШШШШ0ШШШО0ИЗ5Ш-02ШЗ20 Y t ket | st 1 ho 1 A-- «6 6 6 5 6«« 2 W (2 - - L: 5 ;Я 2 - 6 - 5 - 2 --o-. (vehotya | 09551 1 5502053 t ШШШШШШШШШ0Ш00020Ш202753 77

And vohono | here 1 99951 -- 6 (Ж6 FROM Ж" х " Ж y 3-25 ---8- neza | ovai | 559 write no POSHY PON POLON PON HO No KOKON entered | but | 599 100101001100000000,100000001201ТН zach 19599100 70 oz et ШЩS 35 "2 Ш (Ш Ш Ш 2 5BK/KA Ш 2 Е 5 5 5 -А2 4 и lР 2 5 (3 - 2 - х- koorive velor "5 25 3 525 5 6 ( "6 2 : 20 5 6 5 4- I - 2 cont | left | with 10011110 nshshsh 2507 communication 2 2 /--2-5--5----- 5 N ШШШ025Ш0Ш0Ш025И2020Ш0200200-0000020200500 ty 1 in 1 now and 22020207 75 Guyu ve | 55 1 Nishzhshshshshshina drank tires n on its ol ol o kb-3 t tt tt Tnstchoo 5 1 1 7 ishshche- 0 "2" "L i p l lsl lshl by goat | 22

ETHNO PI PAN 7 to t TT TI tt oo ze (S (9 L (ЖЖ (Ж 25 -Ж « I 5 yliBmVShZ 2 SHISH A I Z 2 -4---- - --- (koi om | 55 13110000 now ши "7 vo5oyu1 1 0261 | 9999. | KB- ;йЙЙй4 2 Ж 2Ж LO Ж 6 « 66 6 -« - ; ( - - Ж /|- и 2йл:х? - 2 - - -х-

My Aug. 1 2 5 2 A-25 2 2 Z LO - 2 - 525 - 5 3 . ( Щ 2 2 22 2 I «-2-5- OIOZYUV6 disunion | 05 | ve | 1 now iny I Mon Po Mon PO vevyuuye | ve | ve 11101101 nyshshi Po PON PON POLO POLO

Hiccup! zb 1 yu 13000110 goat | BMW | 55130111 Gozh»v 10311 same 22 | ok koi ra ol 19955 tp In PO shin nn Py z.

Fairy 3000000 ge) snMs snMe SsnMe snMs snMe rBasophils Basophils Basophins vMmmMe vs vMMys vmMmMe vymo vVMMSsM

I'm anti-IE, anti-Ide Tonodurkhaly | anti-IfE | homonym | Hut. cliché antioivE TIovodragno | anti-IvE compound Tryptase Tryptase Ils4 Hexose. Sexosis. Histamine Histamine Histamine Hexose Hexose. histamine Is TME-alpha pAb

Iveyumoi 1 yuyu 1 Sh | 50020170

Event yu 1 yav 1710101011770sh1753005023Ш20Ш20.,0110553-053Ў-0252505330Ў31ГШШ7З0105 "s

Sesshe vo z tr to LA 1 L R 5 LO OO LO LO ZL LO 1 Lo yu EN B5B A --- keyuma | lu | with 7 tt Ge! ее авв ве 202 2 592 2 7 5 2 25 5 ж « ж Х юХ ж «(Ж« ж I ( (I (I «:«й I -

Gaia a--- (Р 5 Ж 5 . - 5 щ 1 | ( Я 2КкК is Р | | - that led SHVZYISHVZOZHAK-Y-ISHCHIVNY I 5 6 ж I I Z 5 I 2 Z 2 5 5 (« 5 5 "(ZhhKBRyu vka blue ze 22 2 Z ---- 2-5 ---------- 2 ------ (ozoz | ozh oyu pinyini PI PNO KONYA NOM VVVNN tot

From Gnuyui I od | 995 | Ш-- --- Ш--О--- write tires p s (boi | 0263. | 9591 55 007 write write aa mit v o Z POKNNNNN UNO UNO NOYA NIKY OKO vyuvet i v 225 - 252 voza | oyu | yayu 10010177 ol « nerve «VTO I | 22 Ll ( (0 «1 ( - 5 Z) ( « Z zh - 07575277 5999 LYNYNYNY NYM POLONYN FIELD POLON Okh NOLOD NV NAAN KOLON OO 400 GE yav | 995 | | tt твювппвпТЯАт ИОИОЗЮО with s вы ет я ---2Ш--2ШBB5-ШВЗРБШШВА Р « « З ША З ЯЗ Я 94 o no0"3 ши я юю 00011001 --2-2.2 52 - 5 Ж 2 2 («Ж 2 4-2 (ЯЗШРТНЬ6f - - (ba; sb 15010110 1 TL (POLO "» ev 1 2 R OO OPTAOSHZ5--5-552----I3Y--IZYBA5Z2A-SHB2Y- 555 vel le 12 OO 2 A-2 2 ST 5 2 ( - - Ж 5 " - Ж 2-25 5И5БИ-55-2---

00001101 Shi Pen Mes WILL 23 ------------Hey Lei 10101017 t o ut 7 o i 1 1 1 1 1 1 1 oo «. 2 2 5 zhK -5 Ж 2 « 255 A -- ko Go | oj ro 99510001 Io shk (Se) b ke bo 65

Table 1 nn ET Y High density of sim sms sms sms snMe Basophils | Basophils Basophils vMmo vim vimo vMMe vmms | vmmMmoemMm malyuonn, aty | vzhnion vit-vv anti-ivE Ionomishkn | anti-IvE | Junominin | Hut. tick anti-IvE ionomidny and acti-IvB anti-1dE compound TLryptase | Tryptase Ilea Hexose. Hexose. Histamine | Histamine Histamine Hexose Hexose. haistamii psa TMEzalfa P-6 rtzez | lo 1 559 pivnnnia MYOnNnnnia NI write now A from 95 ro t 195 11111011 1 | 21202 shk mon PINION 2 1 shishii shi shish shi it 22221 she Ha 17117711 in vbvte ; oh | 735 Go 11110111 17777101 YN ovo be | 95 00710001 10011011 017 nn and! opo | 11 Z - vector 1 55 1525253225ШШШШШ1М-ШШШБ50ЙБ--20ШЙК-ШЗ-Ш052Ш282ВЗК0-20202ОШ205 ШШЗУЗБЗ-О-- 70 С ИМШШШШЩВ- 656 8Я «ЯЗ R 6?T «Р Ля Я ЯТЯ Ю« З((ШЖЯ Я Я Я Я Я Я Я Я Я Я Я ЛИЗВ-ИЗ- 5555 я пссстотвЧ17-- 7 с с 7

My skeleton; i | 2 2 25312 - ЖХЧ - -26 Ж Ж Ж - 1 - :; - yater et S ---52---52552-5--2BY--5Ш2ШБВЗА- 2ВZ2К-- 2 49 9Л Л Е? LO shi Shi svalui i 1-22 2 2 2 RA 2 2 2 2 - 2 « '« «R LIA Ж « I « « : yu yaYae 58-52 E-52:--

AND

Kober ia 2-22 LllLllL TL LIA "L.--SHSHVN- 6 6 6 6 "A.Yu: 252- 6565656 - vo! b 195 | 17011111

That 55 pp of baths is vooboei | 053 55 0031 51.13.31 Sh about | 07171771 77177711 END of schovozh and 9 10011111 1 shi 77 mova |

GG pish shi shin ro nev OM VH SHE S: WIN GO o osppopptss tt re) 011000. 10-11. 11101117 aa 0-2 MA - 5 A--1 - 5 b 12721222 SHY R 32 "L" TO " LL Z LZ TL 2 -.- 7 I-- nn o

Table

Low plen sen Ve poveye vk so PET TET

Analyzed! anti-yE Iscomycin anti-IvB anti-IvE Tonomycin anti-dE | Yuyunomitsyan | House mite anti-vE ionomycin o azntya-ivE antn-IE antay-yaE anti le: ANNA directed 72172221 Oto ee and RR "R A o ship shi Teh! ooo 120201 shee shee 5! 11011011 nin Pr dir! 17001111 .is.is. according to the PN chrya | we | 95 Gog sonne kh nn vyv i pn piva Va po pov po ti, mon revir tia i 7 ----5 (- - Zh ; 5 («j Sh4: Y - - la - - s

Iv | 595 00001001 15 1 yu D YuschB shi shin Pi i | vet | 038 | 9" | (her 15 15 (Her. Sh 15 1. 5sh her (B F1Й 1 1 71 s vat ob Go 101001 01130711010074021ssksps we PI WIN PONNYAh PDNYA ON Oto

ШЩХ-Ь 25 152 252 (6 (-(«( О 6 ("(ЯЖ-Я | (Р ЮЯВЗВИЗ2ИЗ2З2 l7 75200502 535353 рве 35 19511111 10012тн нин

KUAYET'I 5959 22221770 our PI

Kb36759 ox 22217101 above « 55 | 1-11... 1 г нн сх ЛНЙ ШИН ПОВ ПОВООНОНОННОНЯ ВОЛОВОНННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННННН.

ИШ-ШШШШОШБ5Й- 52532-2-2Ш0520Б53Б5-2ШШШШБ30Б--Ш5З2БШЙБ2В-А2ЗШЗБШШВЗВА-2ЗБЩШМ-2З50 20252 2 ЛЯШШЗ тых Catching now the crimes of POKONYA MOONN MON PODANYA p 5; full gender Mon Mon Mon Mon oon NNYA kozh | 0659" 11171101 n" | goats | TO8 195111110 10171171 ” -ШЗБШШШШБ-ШШШБШВВВБШБШБ-0ШИZBY-Ш-Ш0ШЗ-KA«-- со 5 1 711тц лів 555 Нр 5 5. 2 | Я |,.Я Я 5 54 -.("Ш 1-27

SSsZVY NSS PIVNI 2217 UNDER THE FUNERAL UNTIL PNO shi ko nezvvz | о зо -05-52ЗА 5 А 5 52 -5-:55--:25Б5БКА-5КНА--- 2-5 shk 20 (se) 0 25 ko 60 boshe ЧЕ shilnst pd High density syMo sNnMs sMo syMo sNMs Basophils | Basophils Basophils are called MMCs are called vMMs vMMoM business cast | point | bake | anti-IDE | Ionomishchin o) anti-IshE | Ionomycin Hat tick ) anti-i8B anti-EB | dntidE compound Tryptase | Triltase and Hexose Hexose Cystamine. Histamine Histamine Hexose Hexose histamine and TME-alpha pb

Hnat | zm | 99 | Kk | Fri

From yr

Gteayu | b | 51 770317 ---5ИБИА-ЗИВЗЗВБЩЧ-Е-52Б-А5-5БЙ0З52КБ-Б2ШЗ-5335 O-O- ke | and || pov PON KOLONA MONAK COCOON MONA Z ni nozoVyai POOOONNVNNN LANGUAGE PON PNYA KNIFE PON 222-525 411 vva | TO ro GO 11701011 17110010 (vani | her | o» | HER rnee zya-ya----- ЛЯ ТЯ ТТ Я Я Я Я Я Я Я Я 6 - Я 6 6 6 Я Я Я - : 4 - -

Sežez | i and z r 2512 Z A 51 LA SHYU 225 L LA L YA R OO o 70 Gyuz| byu be 11011711 12101171

Ptn yav | i) 25252512 2 L « LO Z МШЖШВБЗ--525Б3Б-А--5ХБК3БЗ8BBBBBY5ZШШ/- МШВБ--- i | yuyu | 1 YOU WASH SOAP OF THE BLOOD OF THE GUILTY IT IS FULL OF POHVnn 271 be | | tn shi oyu pnvTtyu rn om 195 Г111111Ї11711711111117077011170701пипппп (bow | 0519511 NIKOM ZAONININNO TONS NO MNN NNYA PON nt: V PO POLON NN ON NOV p 75 Gayu 81 z | t por ni coasvoi ZAV yy yy

I RUN AWAY. m | r write Mon PI

The plot me | 722 1 PInl FLOWS OF МШМЗБШШШТШБВБЙ--ШВ2Б03|18- pi WHILE PIINANN

И7ОИОЗ95-3 КМВЖЗШЖЖЖВЖЯ---ZKYVKSHKYKA-- 2ЗБ- 6ю(Х.А5 3 353---2Ш2030-5020И-0-5-5-- vet 1 А- Ж - - жЖ - 2 - -

WHAT is that! Я - Ж Е - 2 " - - - - я et 512 5 "Л "ЛАВ -5Z2ZIZHVA-- 5 5 5 5 5 55553555 -533--553К- я 222 RA LA-- 5 5 ж -- - 2 (5 - 5--

Bod SHA YA--O 2 6 - - 6 5 5 - 0 02020202031 1

SsssttY NIB-E STI MOSS SS MON NAOONNNNYA NOANN VAH KONONKO MONO NANNYA dn nbIvn МSH- 2 :ХЯЛПБ5ШВЗОШЗВЗИЙВЗ Z З7: p07OI7O-O- 05-05 vozbnei | 0585 | 59995 | write tires I PO ONY In NIC s -- 5 - --- ---- - 2 n i 2 2 F : -2-------

Table I Ge) снМС сНнМс сиМо снМо снМо Basophils Basophils Basophils vMMS vMMs vim vMMs vMMs vMMsMm given article | Unemitsii anti-IvE viti- VE Ionomicsik vnty-I8E | Isnomycin Hat tick anti-IVE Ionomiynn compound Tryptase | Tryptase and Hexose. Hexose Histamine Hexose. lo v ------ write - U (pov 595 | 99 ST MON PONYNI (Te) veze | 035 | 551 1-1. SHVI OO 2 "EVIL z SsSSLNNY PINNVNNNNYA NOV KOLLONNNH KOLON NOYA mon: hall 7IZ550-53 55 77770107 pi NIM MOL PON PO (o)

Seat roya 0-22 102 020 0262 "TL " "LLRYAYSHSHЩЦЩ8ЩЩШ2ШЩЩ6TVШ628Щ6-2ШВ 2 I t ХьЩьВ- ve mo рр 01110110 яю юю | юю 17712225 531200ШЗ2530ШЗ20-0ШБЗ20-0-500ИШЗ2Ш-0Ш0Ш00И-ШЗЗИ-ШЗШШИШ2015030075 - пе о 25 ( Р 1 «Л Л «ТО Р ОЗ ЛЕІ.ЇЙВЗБ8Б- 6ю65« « УППШ--Т-ШЗЮ5В7---2 в об Го Го010111700700000000201220020тї s rve and o 11111110 7117771 zv SG 811 2-77 210412 toy 1 o 0071 7О5- IMShZ---- 5 5-- so ket i 17222220 g ШЖШБУБИ-ИБ530Б-- already ov 11117001 21703111 PIV PON,

PI ssosvY SHSZ THEM NOANONING FOUNDATION CLONE COLUMN MONO MON 7-52 07202057 повын пи ПН) pol o one write vet t ia --ШШШШШШШВВ---5Й52В2В---:2ЙВИН-.2ИН--

Gyayach 5 1 5222121 ИТШШШ--ИЙЙ2ЙМЙ-- " " (Ш/'«- ЗДЩШШЩЩЩЩЩ-Щ.2-525252ШЩ03--0-20Ш20-- " вв тт я 25477 CURRENT CODE NIC NANONNV FONY vet | b 155 r5-2- 20-20 ШЯ-2ШШШШШЩМИВШБ2ЩЙШ22Ш2-2ШШШШШШШ2ШВ8ИЖ-ЗШШШШВZВБЗ ShTA -l L W 7 -in

Smyk for | 7951 П-55-з И00Й0З0Й- 0-202Й2Й-2055IZBSHISHY-ШЗ2ШШ- s sh- a shi shi shshshishne -- ':- U 2 5 "- 531 - tone bat ve 17 2 2 12 L LO 2 02 LA-SH020SHVZY- 20252-IZVSH0Щ.2.25З20З187Ш « (L 3 ( LP TV Z ( Z («7 « in | on | i 1707 МШШ-ЗЗВУБ8- - 6 9 ю Ж Я«-« Х « Z YAZ -t "» nab ; | o | 5110 | INNO KOKNONNNNNY MON NNNNNYH NONNNONNNNINNH HORSE CANON NOVNYH NOOONNNNINN NOONONO NN NN vobbozv in GO55 |. SHY vpvST svi | om | 55 11711111 | transport | 0.575 99511171 VIM POODINOKI-Z-SH-HIM-51X t YBVBVZB-A--

Go! wow! 9 | 955 | | COMPLETE CURRENT COMPLETE WINE PON NNYA KON NO mines 25271231 ШХХУВ0ВХО- ИЗ- MVSHZSHUSH-

Plots in her 12020211 2 212 512 « 0Й0-0-205- ШХХШВХХВОШЗОЗ t Сю1-4 MVШ---ШФЯ-З5ЯВЫ-0252 2 2 2 5 «t no mon MON 0Ш0Щ2000О- shk 20 is e) 0 25 ko 60 bo

Table

Analyzed anti-IIDE | economically ayatiirE anti YaE | onomycin | to live in paradise | Junomiihmn | Hut cliche | anti-IdE ionomycin | anti-iab | avty-vB znty-VE znin-ivE compound | Tryptase | Triltase Ilea Hexose. Hexose. Histamine | Histamine Histamine Hexose UME-alpha Pe et 8012208 15 515502 17027730 - saw nin r | and 1 ОСС111070711000.11000210027 UNTIL UPDATE OF PN NN direct! 71771110 01 5: Ie nn was called for 0ЙУ-Б-0-0Й0Й-- dog: A NN NAVAN write NN write Mlyn ve te IZZ ("Z LZ Ж 2 ж Ж / -- -- -- А - - -- - :- --x5 Is --5 - - -- - - 25 - - - - - ---« 4 -- (oho | t ngopvnov! io o o o o o o o o:

Petty 25 52 2 « «Я б б0О? I I I I I 6 YAY (ZV 55-55 --- IN - ti aa 2 2 L «2 LIY OR OT OO 2 ROL 62 R «Y LZ LIZH 6 2 SY LO 6 6 F (- nnn ln 4 f « ( Sh (6 («2 2 "- (4Shshchya-I would solve 5 52 5-5 I I LA 552525-5ЙБ-5ШБРКА--Й-ШВ2З--

UN SE 55 11pvpppppotsio i і і і UN PONNY MES nn vovi: | sia 95 705 - exactly! 10001000010100ЗШЗ230М 5 B. A ЗМ 23 -0ЗБЗ05Б5-0-ИШБЗ3-301..01.33537.ЮЮЩД2

GI I la 110 poshi mimy 5-5

Peugeot 51222 2 12 2 Ol ШВШЗШБШ00-02Z 3 (pit of battle 159 10001000. shi p viyu | 9 17955 1711 nin povin GO print ten b i 1 I- 0ШШ-3 MIZ-3 755-525 12 || battle | 95 | sh ККЗ| ТЯ ши равав | бо 19591010 ши ж: и оз 1 я 21 7075205 МШМЗ- - - пЩШЗШШШШБВ30--0-0-О

Iezhiye ba | МШЗ-- 656 9 l 3 Ж " " 5 towers I 12525202 213 ИИ0И0И00И- ИЗИ52З Ш02021202 2 5 ЛИ HOW TO EXIT--- currencies. Н:.::И---И--ЙВ-НИВ-- юнкТЯТт I ПпПЯяй юю | mya 17011110. sr i -- 2-3 rez | shines 5 17001171 Pooovnvnya It is polonyn They Mon Pan

By Go SHVA, SHA OOOPPOPPPppkpEo Her 4

RETURN WHEN COMPLETELY POV NNNn NIOANyNKnn Vin NONNNVnN oto r lz5e | I am | 955

Table 1

Low density High density

Analyzed anti-IeE | Jujuvomycin | yakenivyE vit-IrE. Ionomycin: vntya-Tvye | Yunomyshshyn | Hut. clip vntyagidE Tonomishchnn | anti-IDE | aintn-dE anti-IvE aity-Ive compound Tryptase Travtase it Hexose Hexoi Histamine Histamic Histamine THexose Hazhksoz. histamine iils4 LIME-alpha 1-6 goat | Б |ГО55 17111111 пп яп пе Mon po ШЩШШБЗШБШБШВЯА--35:--- Mon FULLY POOOTONvoih NIK, so 20 7о- pЙ7- ИШШ-Т- - 202 А Т- 5 « « З

KoZ5z 5595 shin r Pon Pi No spades LEGS (ex

Kbi5zE BSSII 11 sewing MY rya | 07173001 write in! m royu 11117010 1 1 1 NI ch-- rya 10102411 1-1 5. 113-411 51 5.6ЖД6.2 555.5 1 svi yy yy sich them WE WATERED MAN PON H NOM shpyast1uoi i i tli 55002024. 11117 7 i 12222-122 0-2ШШБЙ---Ш2ШВ2З3----2ВЗЯ52З28В------52 5 Ш2----55552--- so ya rya g g piky PAVA POHOKINIVNNNIA BEER PONINI KON COKON s royayai 77711 -ОИ7-О- И7И ?2VkOYAYU 5-5 ШШЯ-- 2 '7 (total 177 ШШШШШШОВШ- 5 2 6 | Ш "(ШЯШХЯ( 2 5 " " - ШХН0ШОШ0Ш0000

Go | 66116 MSHVNYIO 2 TL O OT 0IZ5Z5--

Svizher ev | oyaya - 5 5930 zhЩ(-(З -2-2-- 6 5 ( RU; « рю рр р 5 voz526t | 2465 | - | 7 ny | ПИ 20020310 70 я -255-52Ш2ВЗ-2ШВЗЯ-ШВЗ0ЮВШЗ2ЩВА--2ШNB860Ж - - - З - --- З с ил 705-525 ШТЩШШ0ШЗ0- МШЗ-А--« 5656565 3 -И5- rozy | ny shishshshishy 4 shi ch bez! 2 Go GG TYAyago "» goats | va Go 11101117 chic vol i | 95 17711111 11013171 sh

Boz3iyu | oh 95 1 (17071 1 2202177 nose

KO35287 opo g ishL 59 00011701 NT kz Ko152v9 5" 70011031 4

Koz52 5555 PI PIVO NAVY PNO MNN SHVU 0SHNZNNi000111 1 shk 20 (se) 0 25 ko 60 bo

Table 1

Low density of blood cells, blood cells, blood cells, blood cells, basophils, basophils, basophils. AntidE and Ionomycin anti-ryu 0 antibfzh | Monodrachn | iBE acts | Yuyunomishki | House tick | antivn | Ionically strong | anti-ivh | anti-entry | aita-vv | anti-teE sly known. LOOK NNYA NOM PNYA piornorte

Are you gay? ---

Geri yayayu t ya 252 A--2 2 6 LO I 65(ЯЖ Ж : Ж 2 6 Ж Ж "5 (Ж ж 2 | - -- sevneut mat ze 1 2 2 2 2 LA TLAIM-SHVZHIA-2ШЗЖШШШО5- 525252 2 2 2 2 6 565( (5 K«( (СЯ З Z 5 Z 5: as -- ЙБ- Щ2И2ЩН.6.- 6 6 ( -52.-- -3 Й-- 2 2 ( ( (« Я« C 6 ( 6 " ( (I ( From new NS -- 5 -- - 5 5 LIVE 5 ЗХ I" Z " ("5 Z

Ps: VKA: ТZN KSV NEWS FULLY MON IT VOONNNYA - 5 ' ( /( (2 ю Z 5 / 2 2 '- -

Gaya ba 6 2 2 LA LO A TL. LO LA SHIVIY 2 2 SL 6 LLL "I "2 R' " Z Z (« ' 6-2 - ( 5 vezh ba i 2 R 2 ZL R 2 LRL--OSHZY--202Z2-522-2052-55-- 2-2Ш5Й5З2-553-53ГИ--Ш2Ш2К-- then ev vzhut i 2 2 2 2 « R LA-8- 5 Ш ж -BZ- 5 565 5-5 vti 1 6 2 1 12 R A MZA--B- ЖЖЖШ-Ш-Ж-yЙ5-:5---- sign vayakh I tt TT RT I SYA Y "TL 2 2 "LT LIA Y L 5 LI SLYSHZN-SHZ3Z3

Seya at 5 - 52 Y SHCHO- "2 5 65 f:-- svi vyt i 2512 2 L--20251-7 - 5 5 5 5 6325 Sh-Z2Z- - siptsi NI M---1 I- "6t- 62 («F-f : 2 62- - 5 -2 - ГИ-- stv NNYA -- -23'« 5 (Ж-Ж- (Ш (Ж Z Z 2 (Ж- 02 Z 2 2.56 5 5 (Ж ( ( t5 frvyatT 1- 52 - -- - 252 5-5 52 2 20 0.20 :5-5 :655 553 -Z Z B BYK - ev ----4-1 - 6 5 (;IVyuA- ' 2-5 - MZ--- ---- пссхсвнесж НН M- 5 ШВШЧА-ШЩНШ2Ш6- 02 0 ( 6 YaiЭ 5 ( « 6 ( « «Ж - Z Z ( « | Z zl - 5 53535-- MIZ- - Z-- z - 6 6 " 12 2 "TO 6 т Ь I Е Е І I С« 5С"ІІ І Л 6 6 ж І6 І (I Z2 « I I

Ge bat i 1 2 1 LO RAA-IUSH8--2З-52ЗШ-252ЗЗБ-5- 5255 5 252 Ж ж «З о) -- 362-626 Ж ж "« (Ж (Ж (Ж « (Ж | (SHЯ«tZ MSHZA-A-- syag i --20512--2 2 2552 o t "L A- LU MY8- ps ss COMPLETE VANYA MA---ВBYЩщщA- 6 SHЯ- - «- 5 Ж 2ZR-5 Z -

Gyunt yayu r ya ---- Ж ШЯ 49 (З -ЖТШМБВБ8А-- (Ж 2 6 Е seхЕхЕСНИ ПШИ НОНННЯ ПОН МББН-Ж--Ш-- ЯИ-i to MBЖЗЖЗЕ8ВНВ- 6 '5« 6б - б - tzZyu3b M-

Petr yur Y- Щ Z « (« (Я (Я-2З6 52НЕ 5х«Х Я. Yazh:- -- sm - ю« 2 ШЧЧ4 Я 6 « 6 (6. Я Я6 Я Я Я В 6 Х Х - - sia - --

Table 1 -0--- -. sweat (about)

High vigilance sNms sNnMS Ge oi sNnMe sNMe Basophils Basophils Basophilc vMMs vim vMMe vim vMmys vMMseM SHANCHENCH shinivE | iokomshchny | vktivE | chimney | Hat'elyn | pnteivk | assistant | vetetve | znteyave | disappeared o evekiye osn LYN s IA PIV PNYA NNYA she

SS NI NI I-8-6.5Y-K-66-652Й5-26-6.-5252/Ш-26---220БЙ-62ЙВ2К-ИБ5З2--6Й5Б8К--8-- с яр 122022 2 2 L LY L Z "L--SHIVSH8VZSh6-6 6 22ShV2VA-ISHVE- 2 (; ( "Z ХК 6 Ж Ж ж -- ps Nikon NK: SL FULL FIELD - -ZHVA-A- 5 5 "3 gyav ore 2 5;- 4 lyu . - vit son-in-law 1 2 TL LT- РАНТШВШЩЦСНННННТУ6 ШЕ 252Н2ОШ0ШЗОНСШЗВШЗШЗЦІНОШЦН0ШН З - zvy | be 51 1 LO 2 I PA-0252 2 "Р-.-.2ШВ5Й-2-ШВЩВЗ-5Й-5Ш2--ШЩШ5БВ3К--- 1 -

Steey azya I A TT LIA I t TYA TL L YA L HL tT Y I ОЙ Lo ЛЖ Е 6 6 4 ЯШ2ВІ- sty ya t 2 ATO 6 A R LIA TT LM SHVY -2Ш5З- 5 35 3 -Z --SHIVSH-А-- 55555 5 25325532 -BB5БЩВ-А5ШБВВ-А 2 И-- 5 o 9 Mr. ---А---Ш5ШБВЩ---ОШ2ШНБШБШНА АБЗ ЗА /Я /LTZZA-eAN- nisitsyn: ny No M ЙБ- 8-26 62 6Е - :6:- and 252 ::::5-:-552-- -- reve z t ia -- 2 ( SHSHZV-55.25- Ж ж ж З2К(- И-- -3 -2Й0Й2В 5 Ж - И2З 5 (- ПИ8-- veyat | i tyh БКЗА«БЖБЖЗЖББА--К5-4- МЖЗКЖВБЗ-- vet -5565-- --- « du ЖЗБ-BBBBBBBB8BШБА--- ---Ж-Й -5КА- 5-5 53-5-5555Й-- With mother-in-law pe МЗ-- 5 - -8--- hek; ze-12Ш202-2-205205Й-Й5220ШШЩМ-2-2ШВ-2ШЗВВЕК-22ШЯ-2ШХ2В0ШБ-Ш- Ш2Ш2З с --З560)Б- "О ЭСВЖ" " -ЗХ- 7 - - Я - -Ш--- и ЖЗЖБ- 2-5 5 5 565 65 Ж-З52Х- 652 " З Ж - 3«- МЙ- - -

MS--4

Psa NAshoe NA NIE PANI PON ЗЗБЗБ--- МЖББ-6 52 - ее ея- 2212221 ИЖБВ-5353-- -BB-ШЙ2ВЬ-- yap NA -535353353-55353-335ИБ---

Go! k9a0321 3999 va yati I-8- -- 5: : 5 5 2 5 6 Zh : 6 - Zh 2 - :-85 - - -8--.5.-I.- ---353-- - ko tt ; 0Й5- А- («- - (- 6-6565353-3-5353- shk (Se)

F ke bo 65

Table

High frenzy 7 sim снМо сНМе снме сНМСО | Basophil | Basophils Bagophils | VMMS vMMe vMmMe | MMS vMmMms o i vMmMoMm

CHE anti-IeE anti-I8E ionomishny | anti-Ideas; | Yunomishyn | Hat tick anti-IVE antk-IvE compound Triphasa Tryptase lion Hexose Hexose Histamine Hexose histamine togiyui | 005 1.95 Nives with 9 PET I 250--2-5525252525225I2I2IPIPSHBShvshvhvya --- 2.-I2Neshshshshshshshshchvf6yuiuiuiuznznz "Sh07" PIMN NONNYNNONNKY NOMY | 015 95117 111111117111111Ї1117117111110177111111171171171117071771 rum | with | tt uluIy PN PI zhmome | bom | and Gr. (kovo | fight | I 1pNppNss: o TT (sample 02 HER 2 11111711 vyalozh: | b HER 10 uh boi royu her Ch"noYasTt (frogs b15 9 | щЩщ | nshishishnn shi shi NNI DYN NN NIKA kbazae | 0565 | 5959 | | | shshshiishnnishn POLON VO p bi | 99 11111111 shi Op in

Genes damn 11233030 1 A -2 6 2 6; (Ж « '- 6 2 :- 5-5 - - l'-5- min | b | 00011711 1 GO ygizoe boju | 995 | | gl t o SOYAOOOOo26haa t TtTuTh tttyavmiisshhegsya MON PONONNNni KINNNVNNN 7 PsheneN-A I I "LЖ « «ЯЯ«ь тЯ РЯ-А-- «5 b- 95 7Ш575З5 nshshshshsh pany taz | by | 995 | sh | IG shi 71 Po shcho5oi6a | 05 | 999 | | | shi NIM KOKON 71 ssh | 339 Go 11 OO n I ryu 1111Г1С1гоч-по оо 20 | neobh | 035 sia 2 I TT E I " O I MA -2Ш2885Ш52И2Ш2ЩЩ8-- - 4-- 53 be | 795 1 A ooo tt I meter I ИН--52ШВ0ВННВНУЙН6Н6Н6Н6Н6Н8ННИ6О 3ЗЮ Ж « «Й « ЖХХ yava yayu GO! vyuvut yayu ya 2 2 R LI 25 5 L «SYA b S OT b (9L I « « ' 5 32 (voi 365 | v | 71117111 pom o5bo5a | 2005 8005 - 4-- - - - -- - - 2 2 -- 53- pose | Zo | 8755 OH KOKON MON NOHONWon 177 yav write p Mon POLON se 25 pet pyyunundnshdnSTo shu d)

Table 1 !

Neva | there are no shadows and no sleep in the CNS. Basophils Basophils Basophils

Analyzed antichirE | Kyuenomyshchyn | anti-YvE anti-E Ionomytsyan | anti-FOOD | Iyunomishshyn | Hat mite vntn-irE Ionomycin | anti-IVB | anti-IvE anti-IvE anti-IvE compound | Tryptase Tryptase IL Hexose I hexose Histamine Histamine Histamine Hexose TME»-alpha 1 00Ш2З020323231010 10 uko | oz 195995 | | 777 | 1 yav pYzh Nv POLYV ZNO POOO PON Ge ke50348 0066 POMVYN NOKHOON PI Po POLYA COKON PON (vekhzyayu | soot | 9955 | /| vysh Po 1 koBoziya 9038 5595 |. 17 1 pili PIMOI PONYA ON --535353555535353383- - vezozvy | | 0058 9999 | write be 7000010000011700101vvvvvvo3st

St | I | I" | 00177711 2517000 s byu! 00077707 PO uyuzoum | oh 95 | 37001077 70771 o echo | 2539 | (:І |. Mon MON 7771 95037 5 - 5 5БЯА-Ш2ШВВУА-Э52НЕ - СЭТt pi PIL PON POLA ryu 70170СЯАЯЯАохpYalsooppoTtTyuto1 (lucky | b55 | 5» | | Y, .41 5. 5. 7 1 22541771 in kebmo | 3 | 999 | 20202031 73017771 echo YN CHANGE t GO uv 00171111. GG pyv 3 - goat | 055 | 1. NNYA PON: OKO PodInya PI PI s SD Z DES ZYY NIMY ZONI t top vo | Soya Go ro "z ro: | oyu | 99901011 70171777 " ozoa | be | 959 | SG 70000171 8950393 t -- 5 5 2 5 5 : : 52 5 5, | « - 4 ven ----Fi-- shi write MON MON NOV NO NOKHKNNNNVNN and vve --- LY - I COMPLETE PNO NONNNNINONNY NONNNNNNNYA KON KON NIVY . her 20201717 shi ee 11 11111111 you tp ro!

00001010

Low ideality High density

Analyzed anti-iyaE | Junomishnn | vntn-ivE ankhn-veE Ionomycin o) acts 1bE | Young people Hut. cliché auto-IeE TIonostrongly about anti-i2B | Antiv anti-IE anti-IvE sloluka Tryptase | Trnyataza lo Eexoz. Hexose. Histamine Hexose Hexose. 8 rvyyat 1 1-52 6 Bi Z-- roz u 110 113000100020Ш0130003033 055 00000411 кто и ро 2202041 и 4 в шибе -- « Я ШШЩЩ «6 Я Я - 6 6 НЭ Ж « Ж 5 ( 6 Е - Ж - - 95 -- -- - la A LA--SHY5Y85: 5 5---5B5BBK-- 0IZ- ibovyav | yayu | 55 177 МШ- 7 МШЗШ-- PISHV-U-- shaft I I 2 RA I 5 LD.- Y-- ИШЕШШ25 2 t OO llt vbmia 999 | 99 |. polyn field POV POONnnnniya nn NINI 2-51 17 osi she sov v Y VYN --2- 2 6 5 5 5 6 ('lt----eyu t' tv 5 5 5-35 :-51- I -- you by 11070117 (vva | 5599 | 5599 11100100 INNO NOM MONO MY RVE | 595 Go 11111711 MON NEWS NOAONNNANNIYA KONI

NOSh ss NESLY MOL SSEZOYA OAIVNNVNYA COMPLETELY NEW THEY PON ZA shi

Penayet I | I 12722311 735-00-55 05050 I5O5- tone 5599 55010 1330-1051. shi tov) g" zast tr tt tr ky "LL-- 2 (" " - Ж ю "3 b 2 3 - 4 I- ---- mon mon NANNYA

Skeav 1 20201222 2 5553---0-50---205---2Ш2З32И-0ШШШ2--0ШБЗ3Ш--ШБЗ0ИЗ-02ШВБЗБ-5-203-- ШШЗШШВШ0Б0О holidays 52ШВШ--Ш52ШВЗB-52ШШШШ 252 4 I I S I Y I (Ж - 6 6 6 ю9« "I I-

KOBU: 5985 2401 tp

Co)bATE 555 221 MON MONO NIKY PFC NIKY PFC SHE ah | 55 71 177 11011101 byu | I GG 11111 1 tn zhi |) 55 77171111 101 37171717 rev I" 1 020З8032120І2Ш2З5Н2023І00І-02Ш201І0Ш0Ш00010І00Ш00005053 povin Ін shi

B zhi tires tires Z sha 55 GG NsSh;-.oenncht Fi she yy yy oo i 11111710 17770727 ba | 59. pi PI GO GG 23202077 17 half full OO with k9ab345 | 995 | oOONNVy UN UNTIL THE END OF THE COCOON OF THE NOSE, etc

Table

Analyzed! anti-DE | Ionomishna | anteige | anti-BB | Tonomycin | antya-IeE | Junomycin | Hut. cliché) yants-1vE | Ionomizen | vnty-i8B | anti-eeb | aznteidE | zntya-ivE so Z Nina ny -- shi shk po040U ghnya ly NNNN NN PI NY Po Noya oh I it po pon nya po zo vyav 5" 11717111 ONE write polonin No mviyit Z, PSHCHITYSHZSHISH 2 "A YAZ TO--Z With П707О-О-б Ot MY b theme 751 poolllan pok loto Ш8В00О- (zhvyvh in 027113 О025- МЖТШ- (Ж Я6 ( (Я Я6 ЯZ Яю9 9(ЯZ barks I moats 1 7-50Й5235- PNYA POLON BUT HE HORSE -

Seh uyu 195 17777710 05th IISHVSHVSHBUIA-OII2025 2 215 5 appeared in | 951 2332152 3152-53 - SHTSHZY- 5 From Wednesday | | 1 1 1 11010071 reyuu| oh 95 0/1 11111117

ZB | voetosi | 0215 | и-А--2-- 2 2 « «й.ЖЙ6жЖ 6 2 й « 2 2 Ж 2 б 2 2 25 6 :-: 5 - - 52 5-6 - A -4- (ge) (kah | dm 77101111 shish nivy nin vogtoz5 | 0583 PN UNO NOKNVNNOnvnya NN Z shi shi shi veto shk pppnT, PNYA NOKHONNNya NNYA NHIH 9237 1 6233 | 5995 | | yo bota | 15 | 9571 IZ5-i I- ISHНЩ8ЩХVO- lo tt» | a 9 177 A -- 5 26 Ж 6 - МВЖШВИЯШВZШХVA-7 «

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Low fragility High integrity (Se) сНнМС снМС снМо сНнМС сны Basophils | Basophils Basophils. vymo Ka vVMMS MMS vVyMS vMMioM zholisnno| oktshE | horse anti-Eat anti-Eat: | Ionomycin antn-1E | Idnomycin | Let the mite | anti-IIYE Tonomytschin anti-Ir compound | Tryptase | Trnitase and Hexose Texoz | Histamine | Histamine Histamine Hexose Hexose, histamznyts TME-alpha plo what Seyu t ia 1" 1 1 1 write our wormwood ponannnia pong g ko 60 bo anti-1vE Ionmycin anti-ivb o anti-irE antn-veE

Compound griptase riptase Hexose E-alpha P.-6 k908580

Code 08586 9999

I -WOK 5111 Defense: 511777111 KOVA I RYU 11771171 »Ra Ryu 11771 The horse eh 65021711 Languages B 11711111111111111 km Zou Yuyuy VV 17721171 O NUMBER 10770111 It Ron 0101111111 Vietattrya TI: vel: p ryu 11171 i; sewing machine 117711 with a relay plane about a flower 1011 oy" 010111 yu be be b 1171171 zve" re 73807171 ov yr 101 zle yr" 01710111 65 anti-IeE Ionmycin anti-IvE (anti-ieb anti in

Compound Tryptase Triiptase Hexose TMe-alpha (-6 individual la r» 010001 to rai 10011

GENES ANN UNI MONO POZNYA PI

Gosny zny sp NONOLNYA NNYA PAN shih ryu ryu ryu shen re» ryu 01001101 » already she r» 0110101 shazhere re 10111101 believe ryu v zomet r» 12211 o

EESONNNNY UNN SZNNNN NNYA NNYA velo b" 01111 y » Be i 12 21 11 o ven r 17772111 nd ve r o ra 1171171 si kovyu ve 0500 ryu rr z

Contact us by phone: 60117011

Donkey drools sovno vo vo z voi 5010101

DY ny khny slyny ny nin m yu fi ryu 111 zvy r 011101

Phone number 80117011, e-mail address 22252511

ID to send nn non VANYA oyu 3 21220221 1 65

Table 18 anti-IrE Tonmicin anti-iE anti-irb anti-ivE

Rintase compound Tryptase Sexose ME-alpha ShP.-6 "zei vv 1 00710101 veli 1 1 1 1 o vere re 17111111 boishee r r» 01000110011 shime 12251211 shi; mya 172031

WHAT'S AVAILABLE IN NOVEMBER

ESE MNYA NONONNNNYA NANNYA NANNYA NANNYA g tova Fr» 17202011 o gateway 11110111

GETRY UNN POLON KON NNYA NANNYA m "ov i 21222011 y

GENY st NOAH HORSE NANNYA HORSE - boots I 17222211 and in: ryu byu 11700117 she ery 1 4 vot 17713" 5 "7 vot 1011 ov 10077 r" 10 vot me 557111 "DN zvys sv von novo m S ZYSYAI 1 GO oy KUoy ro 329 mos Ohm Bon

Fo bom 151 |011 ov rev 77101771 zsh doz bl ol yuyu |! mot ve Y111 1 tries ref | | her b5 ee SHE BZ KR KATE anti-irE Ionmicin anti-IBE anti-ISCHE /(anti-irv;

Compound "Hryptase Tryptase Hexose E-alpha Sh.-6 "bovtya я007102001.1 shlya 27017721 el» ra 1721151 eovte ra B

ETNNV UNN hSVNYA PNYA NANNYA OLYA sovka r» 11111 vyh re» 1 ote bo be s ho byu 5317111 o

ESSEVNNY ORAL NEW NOW NANNYA NANNYA dove vv 7111 o color 55 in ryu t

SOSNY UNN U ZNNYA NOMNNY VANNYA NNYA - here is 01000111 from window 17777171 Tue 17211711 4 o Tue r 160 2 2 51 2 2 2 2 1 | 2 5 fire 6 2 5 1 1 wolves 1 2 1 Z yuri 1777111 zo Beria 11777717 jew 5510111 tot rya r» 71701 wobbler 82211 oon rai re 100111 uter 11 vot fer» 11700171 65 cNMS cNMSnMS vMMoM oM oM anti-YsE Ponmicin anti-IrE Zanti-iov anti-irb;

Compound Tryptase "Griittase Hexose PME-alpha Sh-6 and higher

K927096 0.402 9999 ШИ se

And oh luck? with cotton wool 530999 tires shsh 8927099 9999. 9999 ge and ny shi and s 8927118 0.065 with shi shi so you in 100.11 « vot fo 17000111 00 ra | 70000101 mot» Baby 01703031 shk more GP vata of yy vaz oyu NI vezzo yayu | I am 65 years old

Riptase compound PERiptase Hexose-alpha (1-6 "ovlia i 10001011 neck ve 17771017 shi" 17222201 bot yayu 10010101 shlya re 10770171 1 sho» ryu 1722311 "iya yah 01700011 shle r" 17701701 hlotyu

In scho svv non nya po po o sli zia 3.201150 i ovte ma 1 2 2 2512 | "5 o el z" 17730111 y

SELEN UNN BY THEM MON NOYA NOYA - I ovtk rya 7310111 and send vv 71077111 4 bot in 12203111

SNY sieto nie nie in yuooooakh r» 17101101 from tya and 21725251. ,1

Phone number 17731711

Foorvlya shi 117202020232310220101 the will of the fairy 17777171 tin vv 17222211

ZI sovy eh VOLYA VOLA OLYA ANYA yiv va 1772 271 2 2 2 2 12 1 bo sh- BE OO DO KIET anti-IeE (onmycin anti-(Eb idnty-eb | danti-1vB

Compound Tryptase Tryptase Hexose TME-alpha | - 6 of them are 11111

GEENIV WONYNY NNYA HORSE MON FIELD

"this was in 1711; yuyu 1221 in Be "ovrya vytryati 1 voy wa EI sya boviyu om 111 shshi shi me 77717771 shy re 711 o di ZSU o NOYA NOYA PON her

SSTESENNY SZstNY NINNNONNYA MON NANNYA FULLY 7

EE YOU VYAP PNYA POL yus s doz obyueoya 111 des oBemo in vo ve 01001101 5 «7 mya 7111 » EEESZNY kny NI PI NN MY voy re 11727221 vo 0oveu By? | shi zo femekha biv || shi byu I 11119999 Po r

Fossination of C us

Tv blya sho |v 111 mu ZY NNYA Sto TEN PON VYN i SEBTO MUST FIELD PNYA PON sh Behara rat | 11111 be

Table 18 snMo snMe vmms o iVmMMs | |vmMo anti-1eE Yunmitsik anti-YobE Ianti-IbE /|anti-YirE

Compound Tryptase riptase Hexose PME-alpha NI.-6 e shi 5" 01100101 vy yayu 110111 g sheya 23120011 yuyu: 26 23101 F shiyu ra - s y E И7ИИО7loo lyu y

Number 9551111, the language is Ray |! GG that I'm a rum | ГГ (Се) овират 01011 воза р я мі рт ІІ somiv рее» ||! yuo dyan b sho buvayu ri /| 70/11 65 PE SHK GLUE anti-IVE Iovmidine anti-TeE danti-IVB anti-IRE

Compound Tryptase Tryptase Hexose TME-alpha ShZ.-6 and "ore 00110001 1 wora sha 01770111 zoshma 17770171 v ve 10001111 shiu re 17700711 "ve ve 01172010 vime ooo 01011117 g vimy 11 jure 5000 on "1011 "v

EE URNS MON KONYA NOYA n wool 02000001 and kimi p

ETHNO FIELD OF NOLONIA NANNYA « yu vy rya 50001113 5 i zn 7 tue r 1211 sib b 12211 zore vv 17702001 th :

For rez byu ov

Backgrounds: ble Y 1. let me call you ooo we GT movne rt! about clothes about | | 171 b5 сНнМо сНнМс vMMs vVMMe vimo anti-ЯE

Tryptase Tryptase Hexose TME-alpha

THE GENES OF USNU YM PON NANYA measure 170101 o narrow my seam ve 11720111 t - goat 5468 0.705 shi m ve ve 250171 th

Rly All MON p NNYA NANNYA koiy shi thy (in 03170031 ore re 11722211 jury in 11722111 65

- STILL BZ BK ET, anti-IVE ionmycin anti-IVE Zanti-TeE /anti-IrE

Compound I Cryptase riptase Hexose E-alpha

SEKASEVIY ET PON KONYA THEY PON

SOASZV SEMY NY PON PON POL and nn shsh

STV sp NN ni NOV MON veto I «S A - 4 oval 1 6 ve35491 0 B,873 ni dez ryu ІІ sia ooo 111111 o dozvaya zo yu rma 11111 iy veze rea! iy "- vot roi 11111 i zoryu 61111111 so uza lat 1111111 node " yuri rzi OV SY ON 13 t" ve r 71 z m tu 1111

F00odevyu voy11Ї111 mooryuzyauee or rony ZL USS MON MON TRU MON

For i toy me 17707171 vol v 11770101 obi 5 01170001 zorya 17771171 ob me 17711011 b5

Tablet IV s- EE SHE SC NOD anti-IrE Ionmicin anti-IvE santi-iyab /-(anti-irb

Compound "Gryptase o Gryptase Hexose ME-alpha ShSH-6 boovam o dv | 17111111

SEE:B EV STI TPNYA POLON PON NO vozi buu 11111 they STELE ST NI PO PO PON PO shi ve 17222211 sho rya 71777171

GENY ANN NN UFO VOM NOYA s ov vy 177111 o vymoy 01000111 uviz 17222201 o

ESE ZE PININYA MON NONOVNNNYA MON y

EEESOVNY UNN POLON NNYA NN NOVA - I bek you 17222111 from she» 05201711 vyh 10711 4

From hundreds of elephants pon he NO ANANNYA

From a new dream, in the world, in the world. Nem hi Slon SS zn noya PON NOV voza poyu 1 5 fbuser ra ov |ЙЙ1 1 ober r2fm6 bom language obbzhobyu 111 65 s- SHE KE anti-I1sE Ionmics antichiab Yvnti-eE anti-IrE

Compound Tryptase riptase Hexose PME-alpha |N.-6 e she B EE R L

ETESUNNY US LNNYNY SUMNI UNN UNN UNN shih you 62 2 10 2 251 Z zoryu r 62310011 shih ro 1111

SSO lSNNY Z NINI MON ON "ovyuto i 17220221 veto mia 11777711 vyuz vyuz 17702321 si "ovyuyu ve 17272711 o shen vv 11771111

Ministry of Science of the United Nations Fr

ENN TZN NI NI MON NOV y ven la 11220000 11 t e State y

Es of the UNSK on the UN Eat 22122011 "Its ME 71777012 5 Soovau in 112222011 that Ryu Wau 101117 mo 17303011 65 anti-rE Tonmicin anti-IrE and anti-E

The compound rigtase rintase IHexose PMe-alpha 11.-6 " izyu fin | 00111 kikh pai 010110 sov sly stan NI PA VANYA zorya kyu dar ki bzhbyu 010101 p vezh pyatoi sho eEtNI NN sny NI NI I

SHY PZU ZY MON POJOHONNNNYA POL s oiveyu or o

THIS IS THE ORAL SZNNNY OF THE LORD OF WINE towers 10001001 F "and 1901011 F

TIV TIRES Spi es PA POL - vyz ryu 11 ii ben all and vet 10000090 10100 4 o i i 00100011 5 s

ZV ss svya py o o o e-mail 01000011

Backgrounds re 01000001 mom SI WITH HIM MR. VANYA p kozh b" ob re 01000011 in the language of rya 01000011 yu yiv m 17700171 b5

-- ZHE Ж B TT anti-TvE ionmicin anti-!vE anti-IaE anti-TvE

Compound riptase riptase Hexose TME-alpha IN.-0 "difficult" 7.1 02011

SSS МНН MON MON NOV NNYA min vo ryu 17111 v rbvzh mer» 11722011

ИШЙ750Й7zvl ti: pryu 0171 » -5Ze8. I'm sewing prya 0231011 I'm sewing fo s zvyra 01000101 o

BV STANI PON POLYA PON PALNYA towers 11212 2 2 2 2 51 LZ 11 F "vve me ryu 17720171 in

NI SN PO NOYA NOYA NOYA - high school 170111 st

ET El NIMY PINNYA PAUL NOYA 4

Y ШЩШЖ535Й7shZuyuOT x s 945405 0.131 y shy i --- b vv 10011011

Fo oveu in" 00177111 jur r" 11770011 with vy r" 0101210

HENNY FROM THE TERMINATION OF THE STUMP OF THE LEG 17770001 1 ve le 11722 21 2 2 51 2 obi mi 17222111 zovr re 17771711 yun me 17720111 65 sh- SHE SHO SE ET anti-IvE Ionmycin anti-IE |anti-ivb |anti-irvE

Compound Tryptase Tryptase Hexose TME-alpha (1-6 with 1

OSY he UN NOYA NOYA POLON in rbee mu 1172001001001

ANN IN: MON HORSE NOAH NANNY še in | 22 2531 2 251 vv pt 2 o

GOETHE UTVYNY POLYNY NNYA PONY NOYA s zame 12222121 o veme were 11222101 is "ovem vv 17777001 o veve 31771111 -

SES UNN NOYA NNYA KONYA NANNYA Bormyria 11722011 and lake | 4 what will I kill111 With seooooozbaahoozvva 11 poooayah ovviO|ІІ11 sho rya me Her 177111 zhi 5 ST ZNO POLON KONYA PON PANNO mash 5 S

Zoya reyahavo LAVA | en r

Fobor I and she I byu obli | 1111 a.m. 0943 a.m. sea west of Laa | HER 1 65 WITH- THE SAME ST DIT anti-IrE onmicin anti-Iof anti-iShb zaneya-ivE

Compound riptase riptase Hexose IM E-alpha SHI -6 s ovoome 01000111 oi kN NI NNYA PNYA PNYA

PLUM VILLAGE MY CAPTURE PON CAPTURE war chariots 111 des rya 1 ves rya 11 tore 111

EEESUNNY UNN NI NOYA KOLON NANNYA doit o vz 1 shi sch boby | 1 shi o wine obo? I'll take the ryu || 111111 F

Y nin SHY F layers 1 - dya ra y m SS Sv M p PO MON y sho min vir with sshooofeyuyuy laya 11

And" what I what Tuesday | v5ryu 1111 va ofeyuyu 1vyu ve mzorvyyu | 7th week of the 1st year 1 eoovvmy 1111 battle ry 17111111 zsho bez ov ryu 111 ov yur" 011111 mooveyua be f65 111 younge B 12212020 65

Table IV sh- A SHE DK dTA anti-1vE Tonmicin anti-ishE zanti-Yirb danti-ire

Compound Tryptase Tryptase Hexose TME-alpha (P.-6 sor veoryu 00100101 vozyv Le dom: ob? ryu 1

NETWORKS OF UNN Nr NANNYA POANNYA yuyu or» 017001 shi sch voy ve 671 o vat lya 1111 vom obG F poyu vyu 1111 F she ve 17700111 - chief 00731771 y boro | 111111 st

UNN COFFINS POVI PON NOYA HORSE I give 551111 With them you | 71 71 7 per ore voi v! 111 in 0vmyu ot yuoyumi 9511111 both vv 11

Fooozeyumi rya ryutova | 71711 vom 111 "ya me 17722311 ooo fiya 011311 "yu young Zoe 10111 bo sim sim VMS vim VMSS a.

Compound Tryptase Tryptase Hexose E-alpha | .-6

SD sel zt von VOVNA VOLYA

ET UL PIVO NOYA NNYA PON yayu in 271111 vravyu 11722251 khz vvryu 0170171 shiv veya 170171

SVO ss slon noya NOYA NOYA NOLNYA hi la i 2 2 1 1 Z

ESAY ZONY PO ANIA POI sch zoiiue ovo in 717111 o sherya" 1011

EEVTSNNV z:liny PON NNYA PON POLYA is "sixth 17 1--25- I ve r" 11777211 -

ESE NNI UNN NINNNNYA NNYA NOYA NOYA y "ya rya 11722201 z veya 11223123 4 pryu 1211 « soft ovi about 1111 ooovyuto I re 7177011 ot v re 1177711 ore I 71007711 vooryayu in 1111 zu ih 5311721

RE from z nn us in Voya? tv i shy shy shy shy ev byu 0100,

MN ts st on NOYA KA OLYA zob i 71722010 in oibeyu ryu 17777711 b5 y Table 18

NM nMS pronounced vVMMs anti-ide Ionmycin anti-ISHE anti-yviy anti-1nE 70 Compound Tryptase riptase Hexose-alpha (N.-6 yuyu ryu 11000111 «ozh ov 17000310, shiyayu 1011011 shiye buu 17701171 y shishih ho 01011011 s me byu 17101111 o ve; ote 71172202031722031001 - s y nn shish shi her 8950515 shi vozov 05 || shi shu « a byu la | shi z

Soovvyutyu vav | 1710 ;with" a dose of shit? her language and dreams and PO yuyu ofma byu -, VoBo52z shi shi and shi

Foooozyuyuyum ram oBez | ОЙ to fdehyukhh ro feyu | | 177

F) ko 6o 65

Table 2

ЖХ Бнсоко density снМе снМС Toxicity Tohsonicity Toxicity | Toxicity high density | dry vigilance | high density | high density high density | high density ZIOgkaye Tagkai VIAV VIV teksoz. riptase histamine ItsA LME-alpha piz Svitlorozsyan. This! Tnsg SU Svitlorozsianv. | Sei Tykeg bio vy PI PO VODO V PON POLYN PO. with them cm and n | POONOONYNNh KON KON same | 77771111 41711111 - 56565 5 5 56 "YVIOVd7p"9)383

A: YOU ARE POLON POLON UNO BUT PON ANOTHER COLUMN OF NEW THEM p: IT POVI OO --- r

Govbbt | PyuknyuvTtjnoipttvЬАСyaohkhkhp rovi | 77777717. dp x9ao tro pop ditches | 07070701 - - - ЖЯ-- then ovbvneye | 77). I live (I - 2221011 ki !/ 7777/1711. 2BV-- - 65 below poured

Go fights 00001177 Mon Ze Y7111011771111

EN WE MM ovi | 07770707. PI Y svia | | 999 ev. 2 --- 5 9 LYa r o R ohrt retriever Ya

NN SUehS t PY 72302177 kyu 17717111 tires shishishshshnnshnishshhnshnny shany nyti 0783 Govaya kez6o at di dya hyu in

Ko21218 0463 2076, ho

And oveiz | washed 0 1jayu. | stump 01 bl. at 568.0 | 356900 10 00010111 usu

EE tr 59911119 111 vo2621o Й- ТЯ Я (- 6 5 6; «-« 5 2 - - ( ЯЯ 2 - 5 Ж 5 Ж - 4 A « 255 5 Sh. 5 5 - - -

We weigh it | | GO 71671171 95 p-va (I 6 (Ch f 4 I 5 "2 - 2 : 5 - 2 - 2-2 29 - - - - - ? 2-2 22 -- 5 - - -- --- - I - - I -y be 5 2 (- 6 2 2 I I I y t ho. 211.7... .9999 ko | ..shD (MK. | vy shk 9999 --- 3 | zh 2 - 5 6 vozi HER 00100010 sh 56017777 2719991... sch

Table 2

Shield High density (o) high density and high density | high integrity | sandy soil) high density | high density ingkai Titkai From VAV hexose. ryptase histamine I1ts4 ME alpha Sh-yZ Svitlorozsyan. Sei Tist So Light-diffusing.| Se!) Tisg Spo roves | 0001777111171171101711011770101711007117 1199 1. 1 959 | 6 ЩЩщ Щ K( vav | 0000/7771 ю 11111111 11111.

And it blows 0000/7711 171 5ю 1 1 99 |. sh sh sh sh sh | wail | 01171711 385.11 06 HER she already | pov | from 17 | you HER about | 77/11 Ge"! vyazmavv | 05 | ов бю | byu | ma | tallow 0 | 11111111 district GO Z I Z Ame 2 OM 5 5 --- z yx - - yu - 252 5 ( z '(| -- - -- 9999 2-5 ---- h- tower | blue | 0235 | bob | bi 1 v | o4yu 17771711 hyu 0 1111111117111ho towers | mine | 124 | 1333. | (:KYU | this | 9995 | ( | shi r-ee Z 2 2 5 "A Zh5 2 - R - "2256 5:45 А - 5 ЖЙЯ" ШХ A 5 6 Ж 2 Я | :l "5 Я

TODAY, NIK ANIN 5199 p vaz | 010 1 damn | her5 | 77707000 | o5o5011 6111111 7 |1yu

Wed yy 5 02 o'clock 00117777

Sen (Z A 2 2 Olyu - 6 ОИ «LA 5 LO OO 52 | 3

Go towers, |. 00 | 250 |. | ho 01 ve 11101111 pa -y- 2 5 (ZAN- y 5 - «5 « I t Shchy 2 - A - -4 A - 2 4 - 4 4 - « - « m «ya. 14 HER yam yam om 77117111 vyeto | hm | hm | mo L hm. | hm Goo2o 0111111 | 2220777 t0 vyv et Tatars Higher Secondary School («Я Ж ж Y («Я Ж ШЩ6 .- - 2 -6-щШ - в) s | vezh | ж... 999 999 995 99 -ZA o 2 652 LA "2 TL 2 " I t 1 TYA | RO y?" vozetma | oyu | 027. 1 006 | | oz 067 S kov 1 -- ' YASHIYA0H Hm 07771111 vyeto | 00071771 EA- y --- ----- 550 2717

And the holidays 00707010 VZA--- - - - - 5433 - I - .-44 0647 -a33 so t | scrap | n uncle | "4 | "1 | me | needle | zv HER br HER 77777771 17111111 io)

ШО Ш Tablypya 2nd shk, shk High density сНМс сс снМс снМо Сны сНнМС Toxicity Toxicity Toxicity Toxicity (se) hexose. riptase histamine Itsa TME-alpha p.1u Svizlorozsyan Sei Teh bio Svitlorozsyan.! SEIY Pressure SO vezo233. | 0577 | two 1056 | ov | 22 4) | veezozi | milestone | and 01010106 15 ІІ rve 5 5 A "o "o 5 H---- write shsh 0.729 nn shshsh rve Z 5 5-5 ZE Z 55 RO O OZZS LA A RA I 2 OO 5 2 SYA ("Z nn shi 8945142 in t i y ly v v v v t Y v p p p p VN | vmyakhyu | 00010177 tire write PU t PO FIELD EN 2795 S-e8---- 25 M I t t A - 5 5 6 - I 35 - 5j 15 - - --; 0567 OIV 0527 o. inhibit the reverse cascade of reactions involving IDE receptors

To confirm that a number of 2,4-pyrimidinediamine compounds presented in the invention exhibit their inhibitory ability by blocking or inhibiting the cascade of initial signal transmission

IDE receptors, tested some compounds using a cell-based ionomycin-induced degranulation assay, as described below. in 7.1.1 Activation of low-density SNMS by ionomycin: tryptase assay

The analysis of ionomycin-induced mast cell degranulation was performed similarly to the analysis of IDE activation

Low-density CHMS (Section 7.5.2, see above), except that during incubation for 1 hour, a solution of 6X ionomycin (bmmol of ionomycin (Zidta I-0634) in MeonH (base) was diluted 1:416 ,7 in MT-buffer (final concentration 2μmol)) and stimulated the cells by adding 25μl of 6X ionomycin solution to the corresponding plates. 7.1.2 Activation of basophils by ionomycin: analysis of histamine release

Assays for ionomycin-induced degranulation of basophils were performed similarly to the method described for the analysis of basophil activation by immunoglobulin (CHE) or house mite allergen (Section 7.5.5, see above), except that after incubation with the compound, the cells were stimulated with 20 μl of 7/0 of onomycin with a concentration of 2 μmol 7.1.3 Results

The results of ionomycin-induced degranulation assays are shown as IC 50 values (in μmol) in Table 1, above. The vast majority of the analyzed active compounds (ie, those that inhibit immunoglobulin E-induced degranulation) do not inhibit ionomycin-induced degranulation, which 7/5 confirms the selective inhibition of the initial (or reverse) IDE receptor signaling cascade by these active compounds.

These results were confirmed for some compounds by measuring calcium ion fluxes in CHMS induced by anti-immunoglobulin E and ionomycin. Testing of Ca? currents revealed that compounds K921218 (10 μmol) and 902420 (10 μmol) inhibited anti-immunoglobulin E-induced Ca? current but had no effect on ionomycin-induced Ca? current (see Figure 4 ). 7.8 The inhibitory effect of the 2,4-pyrimidinediamine compounds given in this invention manifests itself immediately

To test the immediate inhibitory effect, some 2,4-pyrimidinediamines of this invention were added simultaneously with the anti-I(DE) antibody activator in the above cell activity assays. All compounds analyzed blocked IDE-induced degranulation of CNMS to the same extent as observed during the previous s 25 incubation of compounds with CHMS for 10 or 30 minutes before cross-linking of receptors. o 7.9 Kinetics of pharmacological activity of ip migo

Compounds КУО21218, КО21302, К921219, КО26240, к940277, К926742, КО926495, к909243 and КО26782 were analyzed in leaching experiments. During the experiments, CHMS cells were immediately activated with an anti-IDE antibody in the presence of 1.25 μmol of the compound (zero time point), or the compound was washed out followed by activation with an anti-IDE antibody after 30, 60, or 120 minutes. The inhibitory activity of these compounds would drop sharply 30 minutes after their withdrawal, indicating the need for continuous exposure of these compounds to mast cells in order to maximally inhibit degranulation. Similar results were obtained during the examination of other compounds. 7.10 Toxicity: T- and B-cells see 35 The ability of the compounds of this invention to exhibit inhibitory activity in the absence of toxicity (co) in relation to the cells of the immune system was demonstrated in the process of cellular analysis in the presence of B- and

T cells. The analysis protocols are given below. 7.10.1 Toxicity to "Huigkaye (T-cells)" cells

Uigkai cells were diluted to a concentration of 2x10 bU cells/ml in complete ERMI medium (1095 serum of 40 calf embryos, inactivated by heat treatment) and incubated at 372C in the presence of 5956 CO" for 18 - s hours. After that, boOmcl of cells at a density of 7.7xX10 Zcells/ml was added to a 9b-well plate with deep-bottom wells (TS (tissue culture) treated, Soviag supplier) containing bbmOl of 2X compound (final filler concentration: 0.596 OM5O, 1.596 MeonN), mixed and incubated for 18-24 hours at 372C in an atmosphere of 5906 CO". Toxicity was assessed using flow cytometric analysis of light scattering by cells. co 7.10.,2 Toxicity in relation to "BOAB" cells (B-cells) The B-cell line "BAB" was cultured in the log phase in the medium of KRMI1640-1095 embryonic calf serum, inactivated by heat treatment, their I-glutamine, their of penicillin, their streptavidin and their beta-mercaptoethanol at 372С in an atmosphere of 5965 СО". First, VLAV cells were collected, separated on a centrifuge (se) and resuspended in a nutrient medium with a concentration of 7.7x10 cells/ml. Next, they prepared two

Prepare samples by mixing 5 µl of cells with 5 µl of compound in the presence of 0.195 OM5O solution in a 96-well plate with deep wells. The cells were incubated with the compound at different concentrations of the compound at a temperature of 372C in an atmosphere of 595 CO. Toxicity was assessed using flow cytometric analysis of light scattering by cells. 7.10.,3 Toxicity: analysis of cell titer Co (F) BOmcl of cells (1x10b/ml) was added to each well containing 5Omcl of the compound. The final concentration of km filler is 0.595 ЮМ5О, 1.596 МеоОН. The plates were shaken for 1 minute to mix the cells and compound. Then the tablets were incubated at 372С (595 СО») for 18 hours. The next day, 60 5µl of cells were taken from each well and poured into B5µl of Sio cell titer reagent (supplier "Ipmygodep").

The tablets were shaken for one minute and read with a luminometer. 7.10.4 Results

The results of toxicity tests against T- and B-cells, presented in the form of IC values (in μmol), are given in Table 2, see above. With some exceptions (see Table 1), all 65 compounds analyzed did not show toxicity to T- and B-cells at the concentration effective for inhibition.

Analyzes performed on embryonic B cells gave similar results.

7.11 Tolerability of 2,4-pyrimidine compounds by animals

The ability of the compounds given in this invention to exhibit inhibitory activity in doses below toxic for animals is shown by the example of compounds KU21218, KU21219 and K9U21302. 7.11.1 Compound KU21218

K9O21218 has been studied in an extensive program of non-clinical safety studies, which have shown that the compound is well tolerated in rodents as well as other animals. As a result of toxicological/non-clinical studies on the safety of the compound K9O21218, it was established that this substance does not cause such a toxic reaction that requires dose limitation, neither when administered intranasally in non-rodent animals (rabbits and primates), nor when administered orally in rodents (mice and rats) during a 14-day toxicological experiment with repeated administration of doses that several times exceeded the estimated effective doses sufficient for humans. No negative impact on the main indicators of the functions of the cardiovascular, respiratory and (or) central nervous system, studied for the purpose of determining pharmacological safety, was found. In genetic toxicological tests, no signs were found 7/5 Neither mutagenic nor clastogenic potential; adverse effects after exposure to the eyes and skin were not detected. Below is a brief description of the main toxicological studies. A 14-day toxicological study with repeated intranasal administration of doses was carried out in SupotoYidiz monkeys with dosages of 2.1, 4.5 or b,Zmg/kg/day. The parameters of the study included: clinical observations, body weight, food consumed, ophthalmological indicators, blood pressure, electrocardiography, 2o Hematological indicators, clinical biochemical indicators, urinalysis, immuno-toxicological assessment, general autopsy, organ mass, toxicokinetic assessment and histopathology ( including the nasal cavity). No negative effects associated with the use of K9O21218 were detected in any of the research parameters, and the dose at which no negative manifestations were observed was set at the level of 6b, Zmg/kg/day. A 14-day toxicological study with repeated intranasal administration of doses was carried out on rabbits of the New Zealand White breed with dosages of 1.7, 3.4 or 5.Omg/kg/day. The study parameters included: clinical observations, body weight, food intake, ophthalmological indicators, hematological (8) indicators, clinical biochemical indicators, general autopsy, organ weight, toxicokinetic evaluations and histopathology (including nasal cavity). No negative effects associated with the use of K9U21218 were detected in any of the research parameters, and the no-observation dose was set at 5.Omg/kg/day. 7.11.2 Compound K921219 b»

In experimental dose-finding studies, a single oral dose of bOOmg/kg was found to be the no-adverse dose, while multiple (7-day) doses of 200mg/kg/day and above were not tolerated. with

The analysis of the ip mygo ZaiYitopeiPa-EzsNpegispia soybean/reverse mutation of mammalian microsomes (Ames test) showed a positive result for the compound K9U21219 in the analyzer line TA1537, both with and without metabolic activation, which confirms the results of the previous study. No negative effect of the KU21219 compound on any of the other four analyzer lines was detected. It was established that CFU21219 lacks clastogenic potential when studied by chromosomal aberration analysis. « 7.11.3 Compound KU21302 with c Several experimental, untested laboratory toxicological studies on rodents were conducted. The tolerance of mice to an oral dose of 100 Ω/kg for up to 7 days was revealed. :z» A 14-day toxicological study was conducted on mice using oral doses of 100, ZO00 and 100Omg/kg. A dose of 1000 Ω/kg was not tolerated, and a dose of 30 Ω/kg led to the appearance of histopathological changes in the vulva.

The dose, at which no negative manifestations are observed in the study, was set at 1OOmg/kg. A 28-day toxicological study was conducted on mice using oral doses of 10mg/kg once a day, 100mg/kg twice a day, 30mg/kg once a day and 30mg/kg twice a day. Intolerance to the compound ko K921302 appeared at dosages of ZOOmg/kg once a day and twice a day. Lower doses (10mg/kg once a day or twice a day) were well tolerated (the results of clinical and histopathological analyzes are not yet known). 5 years A study on rats using oral doses of 50, 150 and 100 mg/kg for 32 days showed good (Ce) tolerability (the results of clinical and histopathological analyzes are not yet known).

Fo The ip mygo ZaiYtopeiPa-EzsNpegispia soybean/mammalian microsome reverse mutation assay (Ames test) showed a positive result for K9U21302 in the TA98 analyzer line with 59 and TA1537, both with and without metabolic activation. No negative effect of the K9UO21302 compound on any of the other three analyzer lines was detected. During two studies of ip mygo with the help of chromosomal aberration analysis, it was established that the compound K9O21302 lacks clastogenic potential.

GF) 7.12 Bioavailability of 2,4-pyrimidinediamine compounds when administered orally

F More than 50 2,4-pyrimidinediamine compounds of this invention have been analyzed for oral bioavailability. In the course of the study, the compounds were dissolved in various fillers (for example, a solution of PEG 400 and a suspension of carboxymethylcellulose) for intravenous and oral administration to rats. After administration of the drug, plasma samples were collected and studied. The concentration of compounds in plasma was determined by the methods of high performance liquid chromatography/tandem mass spectrometry (LC/MS/MO).

Pharmacokinetic analyzes were performed on the basis of plasma concentration data. Pharmacokinetic parameters of interest included: clearance (CI), volume of distribution at homeostasis (Ug5), terminal 65 half-life (1/2), and oral bioavailability (95U).

Pharmacokinetic studies indicate that many 2,4-pyrimidinediamine compounds are orally available, with 90E reaching approximately 5095 (ranging from 0 to 5095). The half-life varied from 30 minutes to 3 hours. In particular, compounds K940350, K935372, K935193, K927050 and KU35391 gave positive results regarding oral bioavailability and half-life in rat studies. Such

THEREFORE, studies confirm that these 2,4-pyrimidinediamine compounds are suitable for oral administration. 7.13 Effectiveness of compounds in the treatment of allergies

The effectiveness of compounds К9У26109, кКО21218, КО21219, КУ21302, К9У26495, К926508, КОУ26742, КО26745 and

K9U45150 ip mimo in the treatment of allergy was evaluated using a model of passive cutaneous anaphylaxis (PSA) in 7/0 mice. This model allows direct measurement of tissue mast cell degranulation induced by ICH. In this model, animals sensitized to CE are exposed to an allergen, and the change in the permeability of the skin vascular network as a result of the release of histamine by mast cells is measured by the change in the amount of penetration of the dye into the surrounding tissues. Inhibition of mediator release by compounds that modulate mast cell degranulation is readily measured by tissue dye extraction 7.13.1 Study protocol and results

In the analysis of passive cutaneous anaphylaxis, mice were passively sensitized by intradermal injection

IdE antibody anti-dinitrophenol (OMR) (day minus 1). At a predetermined point in time, the animals received the study drug (day 0). The modulatory effect of the drug on the degranulation of skin mast cells was measured after the intravenous administration of UOMR conjugated with human serum albumin (NZA-OMR) together with Evans blue dye. The resulting cross-linking of the ЧЕ receptor and the subsequent increase in vascular permeability, caused by the degranulation of mast cells, was determined by measuring the amount of transudation of the dye into the adjacent tissues. The dye was extracted from the tissue with formamide and the absorption coefficient of the extract was read at 62 Ohm. The inhibitory effect of treatment with the drug was expressed as a percentage of inhibition compared to the effect of treatment with the filler, i.e. as a percentage of Avgo reduction. with

Two compounds were used as positive controls: the histamine antagonist -diphenhydramine and the serotonin antagonist -diproheptadine. Both mediators (histamine and serotonin) are released from mouse mast cells (8) after IDE-mediated degranulation. Both control drugs inhibit the reaction of passive skin anaphylaxis; therefore, cyproheptadine was usually used in subsequent experiments. Cyproheptadine inhibits the reaction of passive cutaneous anaphylaxis with convergent results in 6190-/-495 (8 mg/kg intraperitoneally, premedication time - 30 minutes, number of experiments p-23). 7.13.1.1 Results b"

Dose-dependent inhibition of Ese K-mediated vascular permeability was observed with an increase in the dose of compounds KO21218, KO26109, K921219, and KKU921302. These compounds were used either in the form of a solution (6790

REb/3395 of citrate buffer), or as an aqueous suspension (1.595 Amisei). The results show a pronounced dependence of

Зз5 Between the level of drug content in plasma, the effectiveness of ip mimo, and the activity of ip mygo. The most potent compound, KUO21219, showed activity at a blood level of about 1 Ωkg/ml (6895 inhibition at a dose of 100 Ωg/kg) compared to К9О21302, a relatively less active molecule that reduces plasma transudation by 4295 at a dose of 10 Ωg / kg. Moreover, the duration of exposure to the compound affected the duration of the inhibitory activity. Thus, compound K9U21302, which has the greatest metabolic stability according to the results of pharmacokinetic studies, inhibits vascular permeability for 1-2 hours before the appearance of receptor signals caused by antigen, after which its effectiveness began to decrease. All these data are presented in Tables C and 4.

AND

Efficacy of КО21218, КУ20109, К921219 1 8921302 in the analysis of passive cutaneous anaphylaxis and (ee) Drug Premedication filler Inhibitor- plasma administration (ms/ke) min (μg/ml)

НС ше з - В921218 | Peror. citrate 100 | m 174 0 buffer yuyu 17775017 186 со 6795PEG/З396 and buffer sheshi shishi tia 64 zv 921219 | Peror. | dvicelvoda 15 190 | 68 | 4 of 117921 1 o 1,556 00 Go i |in o KUROY | MeROR. 1 Avizel/water 60 b5

BOARD 4

Duration of action of KU21219 and K9213902 in the analysis of passive cutaneous anaphylaxis s Method Dose Time h » Contents in the box Premedication filler | Inhibuvan- plasma concentration (mg/kg) x pya µg/ml) 30 vro 1,595 60

KK OK | Avishcheuda 0/7 to 20 1 37 | 8

Similar activity of ip mimo was observed in drugs K926495, K926508, K926742, K926745 and K926150, which had the ability to inhibit the reaction of passive cutaneous anaphylaxis when administered orally in a formula based on RES (data not shown). 7.14 Efficacy of Compounds in the Treatment of Asthma The efficacy of compounds KU21218, K921302, K926495, K926508, K926742 and K921219 in the treatment of asthma was demonstrated using a sheep allergic asthma model. Within a few minutes after exposure to an inhaled antigen (Azsagiv zisht), sheep develop bronchostenosis, with the maximum obstruction of the respiratory tract observed during the initial allergic reaction (EAA). Most likely, this initial phase of airway obstruction is caused by the release of preformed mast cell mediators. In addition to the 20 initial allergic reaction (EAK), the sheep model made it possible to evaluate the effect of the exposure of these compounds on the late asthmatic reaction (I AK) and nonspecific hypersensitivity of the respiratory tract (ANC), which develops as a result of local or local exposure to the allergen on the respiratory tract. In sheep, nonspecific hypersensitivity of the respiratory tract (ANC) develops within a few hours after exposure to the antigen, and can last up to two weeks.

The results presented below demonstrate the potential of the analyzed compounds to inhibit the cascade of events that can develop as a result of the release of cytokines from mast cells. Ge) 7.14.1 Research protocol

In a model of allergic asthma in sheep, animals are exposed to the test compound in aerosol form through an endotracheal tube, followed by exposure to an aerosolized antigen obtained from the roundworm, Avzsagiv ziut, to which sheep are naturally allergic. Allergen stimulation leads to direct bronchostenosis (both in 3o initial allergic reaction (EAK) and late asthmatic reaction (1AK)) and persistent non-specific F" hypersensitivity of the respiratory tract. These three characteristics are similar to the symptoms found in people who suffer from allergic asthma. The activity of the tested compound is determined by the change in lung resistance (K,) - which is calculated from the measured transpulmonary pressure, air flow and respiratory volume. Control data for previous periods, obtained from the same sheep after treatment with physiological solution in comparison with exposure to allergen, show a sharp increase in K during the initial allergic reaction, which lasts about 2-3 hours after exposure to the allergen. The late asthmatic reaction gives a less pronounced increase in K,;, which occurs approximately 5-6 hours after exposure to the allergen and disappears within 8 hours after exposure. Twenty-four hours after exposure, the response to a dose of carbachol is measured to determine nonspecific hypersensitivity of the respiratory tract, which is expressed as the dose of carbachol required to increase K | by 40,095 compared to the base 70 value. (This measurement is called the provocative concentration of carbachol, necessary to increase K, by 40095 in comparison with the basic value (RS400). The data are compared with the control data for the previous periods "with respect to the same test subject when the control aerosol was introduced and the effect of Avzsagiv ziut. 7.14 .2 Results

All the analyzed compounds showed the effect of inhibiting the late asthmatic reaction (LAC) and persistent nonspecific hypersensitivity (ANC), and some of these compounds also inhibited the initial allergic reaction (EAK). со Optimal results for each of the compounds, obtained as a result of a number of studies to assess the activity of y

In the case of different durations of premedication and different compositions of solutions and suspensions, are given in Table 5.

The effectiveness of the effect of KU21218 on the initial allergic reaction depends on the composition of the compound, while the greatest effect was observed at the dosage of ZOmg/sheep, introducing a 1095% solution in ethanol by the aerosol method. se 50 Compounds KU26495, K926742, K926508 and K921219, which were used on four different sheep with a dosage of 45 mg/sheep in an aqueous suspension 60 minutes before exposure to the allergen, showed blocking of the late asthmatic response and nonspecific hypersensitivity of the respiratory tract. In addition to these late manifestations, the initial allergic response was also significantly reduced by treatment with compounds K921219, KU26508, or K926495. The effectiveness of the compound KKU921302 was studied using filler 4595 RES 400/5595 citrate buffer. Under such conditions, the compound KUO21302, administered at a dose of 30 mg/sheep 60 minutes before exposure, blocked the asthmatic reaction and

F! nonspecific hypersensitivity of the respiratory tract, but the initial allergic reaction remained unchanged.

The obtained data clearly demonstrated that the mentioned compounds have the ability to block the asthmatic response in allergic sheep. Significant inhibition of non-specific airway hypersensitivity and late asthmatic response was observed by all compounds compared to control data for previous periods. 60 The initial allergic reaction was significantly inhibited by K9U21219, KO26508, and KO26495 (5495, 2190, and Z390, respectively). In contrast, КО21218, КУ921302 and К926742 did not inhibit the initial allergic reaction when using the compounds in the form of an aqueous suspension. b5

TABLE 5

Efficacy of typical compounds in the model of allergic asthma in new-born sheep

Gokeayav 17777736 30 10110020215 30101010 abbbetanoloi00111010166300 10000760

SA----I-6-- 37 4.

GOveyu 7 Gya5 111161 90 88 koi |71117155 |. 66. And 76011777 1 9.

7.15 Effectiveness of compounds in the treatment of asthma

The effectiveness of drugs K921304 and KO21219 in the treatment of asthma was also demonstrated in the model of allergic asthma in mice. 7.15.1 Research protocol

Mice are sensitized to ovalbumin (chicken protein) in the presence of an adjuvant (alum) intraperitoneally on day 0 and day 7. One week later, ovalbumin is administered intranasally to mice - on days 14, 15 and 16 (model with greater accuracy) or on day 14 (model with lower accuracy). Such sensitization and mode of exposure lead to hypersensitivity of the respiratory tract and the inflammatory process in the lungs, which are the two dominant characteristics of allergic asthma in humans. In the mouse model, the response of the airways and mimo is measured with a general plethysmograph, which determines REMN (Eppapsei Raize, Vikhso Eiesigopisv). REMN is a dimensionless 20 indicator consisting of maximum inspiratory speed, maximum expiratory speed, duration of inhalation, duration of exhalation, duration of relaxation, and is considered a confirmed parameter of airway sensitivity.

Allergen response (OMA) is compared with animals exposed only to saline.

Twenty-four hours after exposure, mice are given increased doses of methacholine (a muscarinic receptor agonist), which causes contraction of smooth muscle tissue. In mice exposed to ovalbumin, significant hypersensitivity of the respiratory tract to methacholine was observed in comparison with mice receiving Ge) physiological solution. In addition, a cellular infiltrate was detected in the airways of mice exposed to ovalbumin, in contrast to mice treated with saline. The infiltrate consists mainly of eosinophils and a small number of neutrophils and mononuclear cells.

The use of this model for evaluating small molecular inhibitors of mast cell degranulation has been justified in several ways. First, it was shown in mice with a deficiency of mast cells (MUL//m) that F) ovalbumin-induced reactions depend on the presence of mast cells. In mice with a deficiency of mast cells, sensitization and exposure to ovalbumin did not lead to hypersensitivity of the airways and the release of eosinophils. -

Second, it was found that the mast cell stabilizer, cromolyn, can block ovalbumin c-induced airway hypersensitivity and inflammation (data not shown). The use of this model to evaluate 35 compounds for the treatment of asthmatic reactions, which may be mediated by mechanisms other than mast cell stabilization, is also justified by the inhibitory effect of the use of steroids dexamethasone and budesonide in methacholine-induced bronchostenosis. 7.15.2 Results «

The effectiveness of the KU21304 compound was evaluated when administered intranasally for 10 days in a row, from day 7 to day 70, at a dosage of 20 mg/kg; at the same time, the last three doses were administered 30 minutes before the administration of saline, IV or ovalbumin. KO21304 successfully inhibited ovalbumin-induced airway hypersensitivity to methacholine compared to vehicle-only mice.

In a less precise protocol in which ovalbumin was administered to mice once, on day 14, it was demonstrated that subcutaneous administration of K9O21219 at a dosage of 7 ug/kg in a mixture of 6790PES400/3390 citrate buffer 30 minutes before administration of ovalbumin or saline completely blocked the hypersensitivity of the airways and cellular infiltration caused by ovalbumin.

Kz These results clearly demonstrate the effectiveness of compounds K9O21219 and K921304 in inhibiting the airway response in a mouse model of allergic asthma. 7.16 Compounds of 2,4-pyrimidinediamine inhibit the phosphorylation of proteins in the direct direction of Zuk-kinase in "se 50 activated mast cells

The inhibitory effect of 2,4-pyrimidinediamine compounds on the phosphorylation of proteins in the direct direction from Zuk-kinase was studied with the help of compounds K9O21218, K218219 and K921304 in VMMS activated by Id receptors.

For the analysis, VMMS cells were incubated in the presence of different concentrations of the drug under study (0.08 μmol, 0.4 μmol, 2 μmol, and 1 μmol) for 1 hour at a temperature of 37 C. Then the cells were stimulated with an anti-IDE antibody using the method described above. After 10 minutes the cells

HF) were lysed and cellular proteins were separated using polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (505 RACE). After electrophoresis, protein phosphorylation was determined by immunoblotting as shown in Fig. 7, 10 and 11A-O0. The supplier of antibodies was the company "Sei! Bidpaiipod Tesppoiodu", city of Beverly, st. Massachusetts.

As shown in Fig. 7, 10 and 11A-O, the studied compounds inhibited the phosphorylation of proteins in the forward direction, but not in the reverse direction from Zuk kinase, in the signal cascade of IDE receptors, which confirms the ability of the compounds to inhibit the reverse degranulation caused by IDE, as well as the manifestation of their inhibitory activity by inhibiting Zuk kinase. c5 7.17 Biochemical analyzes show that compounds of 2,4-pyrimidinediamine inhibit Zuk kinase

Several 2,4-pyrimidinediamine compounds were analyzed for their ability to inhibit Zuk kinase-catalyzed phosphorylation of a peptide substrate by fluorescence polarization biochemical analysis with isolated Zuk kinase. In this experiment, the compound was diluted to 195

OM5O in kinase buffer (2O0mmol M-2-hydroxyethylpiperazine-M-2-ethanesulfonic acid, pH 7.4, bmmol

MassSi», 2mmol MpsSi», tTmmol dithiothreitol, 0.img/mol acetylated bovine gamma-globulin). The compound was mixed in 195 UOM5O (0.295 UOM5O-final) with adenosine triphosphate/substrate solution at room temperature. BZuk-kinase (Orziaye, IaKke Riasiy MU) was added to the final volume of the reaction, 2µl, and the reaction was incubated for 30 minutes at room temperature. Final conditions of the enzyme reaction: 20 mmol

M-2-hydroxyethylpiperazine-IM-2-ethanesulfonic acid, pH 7.4, bmmol of MacSi", 2mmol of MpiSi", 70 mmol of dithiothreitol, 0.Tmg/ml of acetylated bovine gamma-globulin, 0.125ng of Zuk-kinase, AmMkMmol of adenosine triphosphate, 2.5 μmol of peptide substrate (biotin--EOEOERESOMEEMI E-SOMN2O, ZupPer

Sogrogaiyop). Ethylenediaminetetraacetic acid (1Omol-final)/anti-phosphotyrosine antibody (1X-final)/phosphopeptide fluorescent label (0.5X-final) was added to the phosphopeptide buffer solution to stop the reaction and obtain a total volume of 40μl according to the manufacturer's instructions (RapmMega 7 /5 SogrogaNop). The tablet was incubated for 30 minutes in the dark at room temperature. Tablets were read on a fluorescent polarization device for "Polarion" tablets (manufactured by Tesap). The data were converted into the amount of phosphopeptide present according to the calibration curve obtained as a result of comparison with the phosphopeptide competitor provided in the tyrosine kinase assay kit (Tugovipe Kipase Avzzau KIii, Ogeep) (supplier "RapMega Sogrogayop").

The results of the analysis are shown below in Table 6: - t - - - - « I YE YE 6 YE YE YE T I TO I - OT I

Table 6

ZK Kinaza ke, Kinaza Buk Kinaza | c reparat pSv (in renarat uC50 and in reparat YaCo (in μmol) kmol) kmol) (o)

K908701 0.022 Ko27060 0.62 8940376 0.067

К9085702 0,038 кого ЩІ 5940380 0,029 со ко908712 0,024 927064 0,466 Кк940381 4999,846 Ф 8908952 9,041 К927069 О.І 940352 0,144 г ж ЗИ - їк908953 0,017 К927977 0,602 940384 9999 пен нн у нн сч к908956 1,178 Ко27078 0,222 240386 19,49 5909236 207 8927080 p254 0000 o4ozv7 3999 so

Ko21219 9,041 927082 Ov 940388 Yu,268

Кк909268 9,125 927083 Ю449 что40389 ШЧе « dit tttnntnia in DY div ho - --. ко09309 0,0 935138 0,229 940390 Щі 999 ЩІ 8 с 8909317 0008 935189 0,354 т945071 0,3 и - ї чжжижиннют--жинню сист "» КО09371 0,104 Кк935190 0,047 Ко945140 Я) к209322 0,141 Кко35191 0,045 Жоа5142 -007 шини оо к920410 0,187 к935193 91 dZ45144 Yu.I: ! t KO21718 0.254 k935194 0.169 K945157 1.762 ! - K926242 1.81 Ko935196 0.265 shto21304 2.017 so 50 K926252 9999 koz35198 0.2 K04.0292

Ід во26321 05049 8935202 0035 8945365 0,465 к926500 0,929 935237 0,046 к945366 0,059 8926501 0,193 К935293 0,047 5945369 1,85 8 що 8926502 0217 К935302 0,027 8945370 1,05 о 8926505 007 Ко35304 0,042 8945371 3 ко 4. І дак ШИ!

K926508 0.097 935307 В K945385 22 60 b5

Table 6 "UK Kinyaza | BUK Kinase UC Kinase I

Drug in (in IPreparation C50 (in Drug C5o (in μmol) | kmol) kmol) ; 926562 9999 К935309 0509 45359 0.035 zt Не26594 0.771 ш935310 р.в 45390 0.009 ! 8926715 0,534 8935366 038 4945391 0,01 (926742 0,076 4935372 0,205 д945392 0,014 8926745 0,093 85935375 2,8 945398 0,182 75 |В926753 0,108 К935391 0,223 945399 0,166 9267570 ІК935393 0,45 45400 17,25 926763 (ВО2а 8935413 0,195 945401 0,007 го В926780 0,107 2935414 0,152 945402 0,418 926782 0,17 к935416 0196 945402 0,418 8926791 0,207 к935418 0,558 К945404 9999 8926797 9999 2935431 0,137 945405 0,168 | см 7 |н926798 9999 к935432 0,05 8945407 9999 | о 8926813 0,405 935433 0,07 945412 0,308 8926816 0,062 8935436 0 ,ов4 Ів945413 9999 | о зо 8926834 0,297 1935437 0,127 в945416 0,515 Ф 8926839 0,055 8940233 0151 2945817 9999 ------- : - - 8926891 0,116 8940255 От 945418 999 ншшн ШВИ ій | сч 8926931 0,255 8940256 ті 45419 27 нини пн патини Sew (EE) 8926946 10218 5940269 685 K945427 0.087 in 26949 0076 940275 0,734 4945473 0,273! sho s 8926968 0.235 k940290 187 945427 so. fields "» 8926970 0057 .

Shshch dvovot rah --x 0038000 veome bo shchi so 5000 Ko26979 0.013 1k940350 0.121 8950367 041 ! s 5926981 0.01 940351 swarms 950368 0.011

F) ke bo 65 rt I I I TIA I T I I I I I I I T I I T I I Lo

AI Table 6 in ZUK Kinase UC Kinase UC Kinase

Preparation 1C50 (in IEpreparation C50 (in preparation CO in μmol) kmol) kmol)

K926982 0.028 940352 r 50373 0.067 !

Ko26983 0.012 Kk940353 0.325 ko50428 127 - - 74t- -' ---- - - «t-- k926984 0.459 k940358 0.023 950430 Yu, 15 I

Ко26985 0.203 ЖКо40361 ЧО 950431 999 926989. 0228 940363 0.006 ИК950440 999

K927016 0.954 Kko40364 0.001 K950466 and

Sh927017. 2351 8940366 0.003 950467 rovo -05- 8927020 9999 Во40367 0013 950468 9999 по27042 0.051 ко40368 0.001 к950473 19.49 7 ог27048 0.002 К90979 о9040439 -

К927049 0.004 к940370 0.069 чо50475 9999 к927050 0.114 ко40371 -643 ико50476 9999 Ii s

Кк927051 FO ko40372 0.253 Жж940376 9.067 | o (do2t7056 0.473 k940373 9999 K940380 0.029 no naianya

These data show that all tested compounds, with the exception of K945142 and K909236, inhibit phosphorylation

BZuk-kinases with IIS parameters in the submicromolar range. All the investigated compounds inhibit re)phosphorylation of 5uk-kinase with ISvo parameters in the micromolar range of F 7.18. Effectiveness of compounds in the treatment of autoimmunity

The effectiveness of certain 2,4-pyrimidinediamine compounds in relation to autoimmune diseases (7) was evaluated on the example of the reverse passive reaction of Artus, which is a model of tissue damage mediated by an antigen-antibody complex, and in several other models of autoimmune diseases and

From inflammation. These models are similar in that antibody to a specific antigen mediates immune complex (IC)-mediated inflammatory disease and subsequent tissue destruction. The deposition of immune complexes in certain anatomical locations (the central nervous system (CNS) in the case of experimental autoimmune encephalomyelitis (EAE) and the synovial membrane in the case of collagen-induced arthritis (CIA) "leads to the activation of cells with surface-fixed Esu K and Ese K, especially mast cells, macrophages, and neutrophils, causing cytokine release and neutrophil chemotaxis. Activation of the inflammatory response initiates downstream effector responses, including edema, hemorrhage, neutrophil infiltration, and release of proinflammatory mediators. In the case of autoimmune disorders, the consequences of such events , caused by immune "complexes, are difficult to detect; however, many studies have demonstrated that inhibition of the Esu signaling pathway

K in these animal models resulted in a significant reduction in morbidity and disease severity. 7.18.1 Efficacy of the compounds in the Arthus reaction in mice with Ip The effectiveness of the compounds K921302, K926891, K940323, 940347 and K921303 in inhibiting inflammatory cascades caused by immune complexes was demonstrated by modeling the reverse passive Arthus reaction (CRA reaction) in mice. - 7.18.111 Model «se 50 Immune complex-mediated acute inflammatory tissue damage accompanies a number of human autoimmune diseases, including vasculitis syndrome, serum sickness, systemic lupus erythematosus (SLE), rheumatoid arthritis, Goodpasture syndrome, and glomerulonephritis. The classic experimental model of tissue damage mediated by immune complexes is the reverse passive reaction of the Artus type.

The CRA model is a convenient IP mimo method for studying local inflammations induced by immune complexes, in the absence of systemic effects. Intradermal injection of antibodies (Abs) specific to albumin

Ge) of chicken egg (rabbit anti-OMA Id), followed by intravenous (IM) injection of antigens (Adv), especially chicken egg albumin (ovalbumin, OMA), causes perivascular deposition of IS and an immediate inflammatory reaction characterized by edema , infiltration of neutrophils and hemorrhage at the injection site. Some aspects of the mouse model of CRA reflect the inflammatory response seen in patients with rheumatoid arthritis, 60 CI, and glomerulonephritis. 7.18.1.2 Research protocol

In this model, test compounds are administered at specific time points prior to the administration of antibodies and antigens. A solution of rabbit anti-OMA dos (500 μg per 25 ml/mouse) is injected intradermally, and immediately after that, an intravenous injection of chicken egg albumin (20 mg/kg body weight) in a solution containing 195 bo Evans blue dye is administered. The degree of edema and hemorrhage is measured in the dorsal skin of the C57VI/6 mouse using Evans blue dye as an indicator of local tissue damage. For control, polyclonal (dO rabbit.

The time interval between the application of test compounds and antibodies/antigens (premedication time) depends on the pharmacokinetic properties (PC) of each individual compound. 4 hours after induction of the Arthus reaction, mice are euthanized and a tissue sample is collected for edema assessment. This model allows rapid testing of ip bypassing the activity of many inhibitors. 7.18.1.3 Results

All studied compounds were administered orally. 70 The drug K9U21302 when used in doses of B5Omg/kg, 100Omg/kg and 20Omg/kg 60 minutes before the administration of the antibody/antigen complex to C57816 mice demonstrated the dependence of edema formation inhibition on the administered dose (49.995, 93.2905, and 99.195, respectively). Moreover, the drug KO21302 demonstrated not only prophylactic inhibition of edema, but also therapeutic efficacy, as evidenced by the inhibition of edema by 77.59 when the drug was administered at a dose of 10 Ωg/kg 30 minutes after the administration of the antibody/antigen complex.

K940323 and KU26891 were shown to be effective in inhibiting edema by 32.495 and 54.995, respectively, when administered at a dose of 200 mg/kg 60 minutes before antibody/antigen administration. These compounds are much less bioavailable when administered orally, and systemic exposure levels were approximately 50-fold less than those of CFU21302 (data not shown). The drug K9O40347 provided inhibition of edema by 8995 when applied at a dose of 10 Ω/kg 2 hours before administration of antibodies/antigens.

The drug K9UO21303 demonstrated the effectiveness of inhibiting edema at 10095, 10095, and 93695, when applied at a dose of 200 mg/kg and administered at 30, 60, and 120 minutes. A dose-dependent inhibition of 65.495, 81.295 and 10095 was also demonstrated when this drug was administered at doses of B5Omg/kg, 10Omg/kg and 20Omg/kg, respectively. The results of the conducted research are shown in Table 7. s o (Se) (22) "-- p

From so - s. and? so ko - (Se) (42)

F) ko 60 b5 sew (p RA Ya

Table 7 mg Concentration

Inhibition | of plasma 5 ZEM control (no/ml) filler 70 Drug | Dose (mg/kg) Time Size Effect - time of premedication | edema and premedication (hours) standard 4 hours error 50 y BbbzhbA 0 Пм9жи72 940323. р 0.5 55-93 рЗзх 618 1 524130 878 ж 735 с о и 26.9 11.2 Щ8О2 434 borty rat Z Ф

F

150000 rvmjoe Bvbio - with oyu 0005 00 photo Vzzhtve sch p o 2653 zh 833 (he) ro rents biv g PI ZLE EN STE " is 00 stttrvyam yun z ram riv y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y y

F) yu kogo347 00 05 Vblzh224 (596 485 65

Table 7 | that Concentration! Inhibition | plasma 5 ZEM control (kg/ml) filler and 70 Drug Dose (mg/kg) Time Size Effect - time of cremedication | edema Ж premedication (h) standard 4 hours error 18 00000000 85 З014ж590 2000000 vve 1992k247 k940363. 100 0.5 16.4 510.9 1 67.6 12.1 M2zh5 2 52.3 25.7 37-15 s dv Ve 50000000 Bbzhiya 1755 2 310 o 100 1 o1 14 251-712

Kk940363 100 1 61 z 8 625 3-60 (se) 8927070 "PI NI 1417.29. 1077 5 296 - zia B935429. 50 515149 64289 so 100 5 13.8. Rob 115 5 ЖО27087 04144 r)

In 4935451 lo 008 I44zhi3.3 Pai z1.8 3000008 306154 78.0 32.0 yu 7 vm 65

Table 7. Concentration

Inhibition | plasma of the Earth! control (ng/ml) filler

Drug "Dose (mg/kg) Time | Size Effect - time of premedication | swelling | premedication I; (h) standard error 4 hours 00014005 and 0ю010011115 р 940347 100 and at 100 и Нв

SKAT WE ARE WE

TONNY PI TENY U g 71107 o

Note: "nv-undefined F eEM-t (o)

M-standard error of the mean value 7.18.2 Efficacy of compounds in modeling arthritis induced by anti-collagen antibodies in mice -

The efficacy of KU21302 against autoimmune diseases was demonstrated by Su using a mouse model of collagen antibody-induced arthritis (CAIA). tlV2l Model co

Collagen-induced arthritis (ICA) is often used as an experimental model of IS-mediated tissue injury. The use of type II collagen in mice or rats leads to an immune reaction, which is usually accompanied by inflammatory destruction of the cartilage and bones of the distal joints and swelling of the surrounding "F" tissues. SIAs are often used to evaluate compounds that may be potential agents for the treatment of rheumatoid arthritis and other chronic inflammatory diseases. but) c Recently, a new technology for simulating CIA has emerged, according to which antibodies to anti-type I collagen are used for the induction of CIA "mediated by antibodies. The advantages of this method are as follows: a short period of time for the induction of the disease (development occurs within 24 -48 hours after intravenous (IM) injection of antibodies); arthritis can be induced in both SIA 75-susceptible and SIA-resistant mouse strains; the procedure is ideal for rapid screening of anti-inflammatory co-therapeutics.

Kz Mixture of monoclonal antibodies Agipgodep-SIAF, inducing arthritis (supplier Spetisop Ipiegpaiopai

Ips.) is administered intravenously to mice of the VaiIB/s line (2 mg/mouse) on day 0. After 48 hours, an intraperitoneal injection of 10 omcl I RZ (25 μg) is administered. On the fourth day, swelling of the claws may be observed. On the fifth day, one or two paws (in particular, the hind limbs) begin to redden and swell. On the sixth day and during the next 1-2 weeks, redness and swelling of the paws continue to be observed. In the course of the study, clinical signs of inflammation are recorded to assess the amount of swelling of the paws. The degree of severity of arthritis is determined as the sum of indices characterizing the condition of both hind legs of each animal (the maximum value of the index is 8). The degree of inflammation in the specified paws is determined by measuring the diameter of the paws. They also monitor 59 changes in body weight.

F! Animals are administered the drug from the moment of induction of arthritis, i.e. starting from day 0. Test compounds and control compounds are administered orally (PO) once or twice daily, depending on the predetermined pharmacokinetic properties of each compound.

At the end of the study (1-2 weeks after the induction of arthritis), the mice are euthanized, a transverse 60 foot incision is made at the distal tibia using guillotine scissors, and weighed.

The mean value-standard error (SEM) is determined for each group every day according to the clinical indices of each individual animal, and at the end of the study, the weight of the hind paws for each experimental group is calculated and recorded. A histopathological evaluation of the paws is also obtained. v5 7.18.2.2 Results

The use of K9U21302 significantly contributed to slowing down the development of arthritis and reducing the severity of this disease ((p«0.005), as evidenced by changes in the average values of the daily clinical indices of arthritis (Fig. 12).

Values of daily clinical indices of arthritis from day 4 to 14 in the group in which the therapeutic drug was used were lower by 71-9295 in comparison with the control group (in which only the control was used

Filler). The degree of inflammation of the paws, determined by measuring the weight of the paws, turned out to be smaller in animals treated with the drug KU21302 compared to animals of the control group (Fig. 13). At the end of the study, the degree of swelling was determined by measuring the weight of paws, and a decrease of 99.995 was established in the group of animals that were injected with the drug KU21302 in comparison with the average weight of paws of mice of the control group (p«e0.002). 70 Histopathological evaluation of the removed paws showed the presence of pronounced synovitis, characteristic of SIA. While significant lesions were observed in animals treated with saline or vehicle, the severity of lesions was less severe in the group of animals treated with K921302. Swelling of the joints with pronounced proliferation of synovitis was observed. Growth of fibroblasts with dense infiltration of neutrophils, lymphocytes, mast cells, macrophages and plasma cells was also observed. Vascular 7/5 proliferation was observed, which was accompanied by hyperemia, hemorrhage, and edema. The presence of pannus formations in the joint space and cartilage destruction was observed. In the group of animals treated, the condition of the joints was almost normal or with slight inflammation that did not spread to the cartilage.

Table 8. Average group histopathological index (0-15)

Treatment Mean Cumulative Index xRMS DEVIATION

Physiological solution 9.8 22,

Filler 9.3 4.5 s

K971307 (100 mg/kg), twice a (o) day 5-19 7" Vroroiuzassiagide - lipopolysaccharide (approx. translation) 632 (se) b "--

None 0-00 s so

An average of 2095 reductions in clinical indices of arthritis and paw edema were observed in animals administered COBO twice daily at a dose of 100 mg/kg compared to untreated control animals (vehicle, p-0.1). There was an inhibition of paw edema by approximately 2695 compared to control animals (where filler was used), as determined by hindlimb thickness measurement (p-0.1). KO50 in a dose of ZOmg/kg had no effect on arthritis. from c Drug KO70, which is a salt of KOBO, when used in doses of 50 and 10 Ωg/kg twice a day, inhibited the clinical disease by an average of 39.7595 (p«0.0002) or 35.28905 (p«0.0004) respectively, in comparison with the control with means (filler). There was a decrease in the thickness of the legs by about 50905.

The drug K429, which is a salt of KZ63, when used twice a day in doses of 50 or 100 mg/kg, demonstrated inhibition of the clinical indices of arthritis by an average of 23.8195 (р «0.05) or 20.8295 (р-0.05), respectively in comparison with the control agent (filler). A decrease in the thickness of the paws was also found.

When using KZ347 twice a day in the tested doses of 30 mg/kg and 1000 mg/kg, no effect on arthritis indices was observed. - 7.18.3. Efficacy of the compounds in rat modeling of collagen-induced arthritis

The efficacy of K9O21302 against autoimmune diseases was demonstrated (Ce) in a rat model of collagen-induced arthritis (CIA).

Fo 7.18.3.1 Description of the model

Rheumatoid arthritis (RA) is characterized by chronic inflammation of the joints, which leads to irreversible destruction of cartilage. The synovial tissues of patients with CA are abundantly covered with immune complexes containing dO. The role of these two immune complexes in the etiology and pathology of this disease remains unclear, but it has been established that 1C interacts with hematopoietic cells through Esu K. (F) SIA is widely used as an animal model of CA, which causes chronic inflammation of synovitis, which is characterized by pannus formations and joint degradation. In this model, intradermal injection of natural type II collagen emulsified with incomplete Freund's adjuvant induces inflammatory polyarthritis within 10 or 11 days and subsequent joint destruction after 3 to 4 weeks. 7.18.3.2 Research protocol

On day 0, syngeneic rats of the GO line) were injected with natural type II collagen, and the effectiveness of the drug KU21302 was evaluated according to the prevention scheme and the treatment scheme. According to the compound prophylactic study protocol, vehicle or different doses of KO21302 were administered orally starting on the day of immunization (day 0). According to the protocol for the study of the therapeutic effectiveness of the drug, after the development of clinical signs of arthritis, treatment with oral administration was started on the tenth day

KU21302 at a dose of ZOOmg/kg daily until the end of the study (day 28), when the animals were euthanized. According to both protocols, clinical indices were recorded daily, and body weight was measured twice a week. On day 28, X-ray data were obtained and the level of antibodies to collagen II in serum was measured with

With the help of EPIZA analysis" (7 Epgute I ipkei Ittipozogrepi Azzau - solid-phase enzyme immunoassay (adv., trans.)) 7.18.3.3 Results

On the tenth day after the start of immunization, the rats developed clinical SIA, as evidenced by the growth of indices of the course of arthritis (Fig. 14). In the case of vehicle-only rats, the average value of the 70 index of the course of arthritis gradually increased after the tenth day, and reached 6.75 0.57 on day 28. In the case of animals that received a high dose of the drug K9U21302 (30Omg/kg/day) from the day of immunization (day 0), the mean clinical index was significantly lower (p<0.01) from day 10 to day 28 compared to the index of the control group (which was injected with filler). Rats dosed with KU21302 at the baseline dose of ZbOmg/kg had a significantly lower arthritis index starting on day 16 and continuing until the end of the study on day 28. 75 radiographic analysis scores (on a scale of 0-6) obtained at 28 day, were 4,840,056 for the vehicle group, compared with 2.5 -0.016, 2.4-0.006, apa 0.13-0.000001 for once-daily animals at a dose of 75, 150, and ZOOmg/kg/day, respectively, according to the prevention scheme, and 0.45-,031 for animals to which a single dose of the drug in ZOOmg/kg/day was applied daily from the onset of the disease. Treatment with the drug KU21302 at a dose of Zb0Omg/kg/day for prophylactic purposes (during immunization) or after the onset of the disease helped to prevent the development of erosions and reduce the swelling of soft tissue.

Similarly, treatment with the drug K9U21302 contributed to a pronounced decrease in serum antibodies to anti-collagen II (data not shown). 7.18.4 Effectiveness of compounds in the treatment of experimental autoimmune encephalomyelitis in mice

The effectiveness of the drug K9O21302 against autoimmune diseases was demonstrated in a mouse model of experimental autoimmune encephalomyelitis (hereafter EAE). o 7.18.4.1 Description of the model

EAE is a useful model of multiple sclerosis (M5), an autoimmune disease of the central nervous system caused by immune cell infiltration of the white matter of the central nervous system. Inflammation and subsequent destruction of myelin leads to progressive paralysis. As in human disease, EAE is accompanied by the activation of peripheral T cells autoreactive to myelin proteins, such as myelin basic protein (MBP), proteolipid protein (PIP), or oligodendrocyte myelin protein (MOE). Activated T-cells, specific for neuroantigens, penetrate through the blood-brain barrier, causing infiltration of focal mononuclear cells and demyelination. EAE can be induced in a susceptible line of mice by immunization with myelin-specific proteins in combination with an adjuvant. In mice of the ZL line used in our study, paralysis of the hind paws and tail is observed on the 10th day after immunization. The peak severity of the disease is observed between the 10th and 14th day, and a cycle of partial spontaneous remission followed by a relapse can be observed up to the 35th day. The following results demonstrate the potential of the study drug (K921302) to suppress disease severity and prevent relapse of disease symptoms that may be due to Es in "

K-mediated release of cytokines from immune cells. 7.18.4.2 Research protocol - c According to the EAE model using mice of the ZU line, each mouse was sensitized with the drug RI R/SEA h (to induce EAE in four places on the back of the mouse, a total of 0.02 ml of emulsion containing -» 15 omkg RI P139 was applied -151 with 200 μg of SEPA in 0.05 ml of hemogenate). According to the protocol for the study of the suppressive properties of the drug, vehicle or different doses of KO21302 were administered orally starting from the day of immunization (day 0).

According to the treatment protocol, at the beginning of the disease, the animals were divided into groups with similar average clinical indices and orally administered filler or different doses of the studied drugs with different frequencies. In both protocols, clinical indices were monitored daily, and body weight was measured twice a week. - 7.18.4.3 Results 20 On the 10th day after immunization with RI R, in mice of line 5). clinical EAE developed, which is evidenced by the increase in their mean clinical indicators (Fig. 153. The rate of paralysis gradually increased in animals that were injected with only filler from the day of the start of immunization (day 0), and on the 14th day it reached the highest value of 5, 1-0.3. At the peak of the disease (day 14), the mean clinical score in animals administered daily 10Omg/kg once or twice a day was significantly lower (p«0.05, 4.34-1.3 and 4.3-1.4, respectively.) On day 16, all animals showed remission of moderate symptoms, which is characteristic of the EAE model using mice 5.

Significantly lower clinical indicators in animals that received 100 mg/kg of the drug KU21302 twice daily did not change (p<0.05) throughout the experiment until the end of the study on day 30, when the animals were killed. These lower scores throughout the experiment are reflected in a significantly lower total disease score (SDI) and increased total body weight score (BWSI) as shown in Table 9. In the vehicle-only group of 60 animals, 2/5 mice relapsed. In the group of animals that received a dose of the drug 1O0Omg/kg/day, relapse was observed in 3/8 mice. None of the mice treated with twice daily 100 mg/kg relapsed. b5

Table 9

Females 5 L., which were injected with the drug Virdei 921302, began to sleep from the day of immunization in a dose of 150 μg

RI,R 139-151/200 μg MTV (SKA)

Incidence Onset Peak Level of comorbidity disease mortality

Control 10lo 11.8 0.5 510.3 lo 53.2 i PII z 70 Riasero 71 6.4 100 mg/kg 10/10 12307 4313 lo 441 Zh 1244zx

Once every 14.5 6.0 days 100 mg/kg 10/10 IZO F 4314 zl 33.7 V 133.5 F twice a day

Note;

SOI - Cumulative Morbidity Indicator until day 526

SU - Cumulative Weight Indicator until day 423 a- Lethality not related to EAE, as a result of injury during feeding or death of tidvocephalic animals.

B-Significant difference between the control and experimental groups (р 0.05), determined by the criterion

Student's (assessment of the existence of a difference between two groups, but not the direction of the difference).

For mice 5), which were injected with the drug K9U21302 at the beginning of the disease (11 days) at a dose of 200 mg/kg twice a day, a significant decrease (p-0.003) in the level of the SOY indicator was demonstrated (53.5 -16.9, compared to Ha 72.9-48.9 in animals that received only filler). Moreover, there was a significant reduction in the number (5) of relapses in K921302-treated animals (2/12) compared to the number of relapses in vehicle-only animals (7/11). The results are summarized in Table 10 and Fig.16.

Table 10 and (2)

Females 5.P, which were injected with the drug Kirei KO2I3(02) from the onset of the disease

The average is the index at. peak number Relapse of CO see morbidity and mortality during the use of the disease of the drug CO

Control of pli 3916 zozho4 ol "oo 200 mg/kg 535 « twice on 12/12 341.6 4307 112 2/12 169 With s day and R 1.00 9.48 0.02 0.97 0.055 0.003 "» Note:

CI - Cumulative Index Disease to day 127 7.18.5 The 2,4-pyrimidinediamine compounds provided in this invention inhibit the activation of T-cells io) 7.18.511 Description - The ability of the 2,4-pyrimidinediamine compounds provided in this invention to inhibit activation of T cells, has been demonstrated using various assays using digKai T cells and primary cultures (se) of T cells. Inhibition of Chdigkai T-cell activation in response to T-cell receptor (TCR) stimulation was measured by quantifying the up-regulation of the cell surface marker СОб9. Inhibition of primary T cell activation was measured by quantifying the release of cytokines, including tumor necrosis factor alpha (TNF), interleukin 2 (II-2), interleukin 4 (1II/-4), interferon gamma (IeMa), and granulocyte-macrophage colony-stimulating factor factor (OM5eR), in response to co-stimulation of texoa28.

GF) 7.18.5.2 Study of inhibition of activation of T-cells of the Uigkai line

T-cells of the human digKai line (clone M) were routinely cultured in KRMI 1640 medium (supplied by Meaia(es)) supplemented with 1095 fetal calf serum (EV5, supplied by Nusiope), in penicillin and streptamycin. The research process was carried out for three days .

On the first day of the study, the cultured cells were centrifuged (1000 rpm, 5 minutes) and resuspended at a density of 3.0X1OU cells/ml in ERMI-BO»E EV. On the second day of the study, the cells were centrifuged at 1000 rpm for 5 minutes and resuspended in KRMIN5UE EB5 at 1.3X105 cells/ml. 8 µl of this cell suspension was introduced into the wells of a 9b-well plate with deep bottom 65 wells (supplier Sogpipd). 85 μl of the compound or KRMIN5Oy EVZ solution (for control) was added to each well of the tablet and incubated at 372C for 1 hour. Then the cells were stimulated with anti-TSK (C305).

B5OOng/ml by adding 8X solution in 25 μl to the cells of the tablet. Then the cells were incubated at 372 for 20 hours.

On the third day of the study, the tablets were centrifuged at 2500 rpm for 1 minute on a Wesktap 55-6K centrifuge, and the medium was removed. 500 μl of staining solution (1:100 solution of anti-CO69-ARS antibody (supplier Vesiop OisKepzop) in phosphate-buffered physiological solution ЕВ5) was added to each well, then incubation of tablets was carried out at a temperature of 42С for 20 minutes in the dark. 15000 μl of buffer (phosphate-buffered saline 295 EV5) was added to each well, and the plates were centrifuged at

ЗО00bob/min for 1 minute. The supernatant was removed again, and the sediment was resuspended with gentle stirring. Then 7 Bbmcl of phosphate-buffered physiological solution 296 EVZiaACytofix (dilution in a ratio of 1:4) was added, the tablets were gently shaken and wrapped with aluminum foil. The cells on the tablets were analyzed using a flow cytometer connected to an automated liquid delivery system.

Different concentrations of the test compounds were compared with the solvent to determine the index of inhibition of 75 ISbo T-cell activation for each compound. Representative values of IC 50 for the 2,4-pyrimidinediamine compounds of this invention are presented in Table 11. 7.18.5.3 Isolation of primary T cells 2E8-4E8 PBMC or proliferating T cells grown at gi/-2 from healthy human donors , suspended in phosphate-buffered physiological solution, centrifuged at 1500 rpm for 8-10 minutes and re-suspended in 100 ml of complete KRMI medium (195 Rep-Ziger, 195 I-Glutamine, TOMmol NEREZ).

Cells were introduced into T175 test tubes (372С, 5956 СО"), and monocytes were left to bind for 2-3 hours. After binding of monocytes, unbound cells were collected, counted with a hemocytometer, washed several times with phosphate-buffered saline, and resuspended in Uvzei's complete medium (Iskov's medium in Dulbecco's modification with 195 human AB serum, 195 Rep-Ziger, 195 I- Glutamine, Ommol is 25 NEREZF) with a concentration of 1.5 4U cells/ml. Then 3 µl of diluted cells were added to compounds diluted to 2X in U5zeI medium and incubated for 30 minutes at 379 (5956 052). After this procedure, the compound/cell mixture was transferred to stimulation plates as described below. 7.18.5.4 Research on inhibition of cytokine production in stimulated primary T-cells

Stimulation tablets were prepared by applying to 96-well plates 5 μg/ml of POP (supplier. "o 30 vo Rpagmipdep, catalog number 555336)-10 μg/ml, 2028 (supplier Vesktap Sotseg, catalog number b

IM1376) in phosphate-buffered physiological solution (in the absence of Ca?/Ma?) at 372С (596 СО») for 3-5 hours. After incubation in the presence of stimulating antibodies, the mixture was removed, the tablets were washed three times with phosphate-buffered saline before adding the mixture of primary Ha

T cells/compounds. 35 The mixture of primary T cells with the drug was added to the stimulation tablets and incubated for 18 hours at 372°C (595°C). After cell stimulation, approximately 1500 μl of the supernatant from each well was placed in 9-well filter plates (Sogpipda PMOR filter plates), centrifuged at 2000 rpm for 2-3 minutes and immediately used for EIG IZA or analysis | OMIMEH was frozen at -802C for further use. The EGISA analyzes for 1-2 were carried out using the Otsapiikipe Nytap 1-2 EGISA kit (supplier KO no) from Zuvietv, catalog number 02050) in accordance with the manufacturer's instructions, and the absorbance was measured using a spectrophotometer at a wavelength of 45 Ohm. After subtraction of noise values, absorbances were converted to pg/ml using a calibration curve.

Multiplexing of immunoassay I type for TME, 1-2, ZM5SE, II-4 and IRM9 was carried out in accordance with the manufacturer's instructions (Orziae Vioyesppoiodo). 5 µl of the sample was diluted in 500 µl of the experimental solvent and 5 µl of incubation buffer, then incubated in the presence of 1000 µl of a diluted solution of diagnostic antibodies for 1 hour at room temperature in the dark. The filter tablet was washed twice with buffer for - washing, then incubated in the presence of 100 μl of diluted secondary reagent (ZAM-CRE" ("7 Zigeriamidip

K-RPpusoeguiyip - Streptavidin K phycoerythrin (adj., trans.))) for 30 minutes at room temperature in the dark. Finally, the plates were washed three times and measurements of labeled microspheres and fluorescent

KRE with the help of the device of the company I itipeh. b We compared different concentrations of the compounds with the solvent and established the IC values, which characterize the inhibition of T-cell activation of each studied compound. Representative IC values for the 2,4-pyrimidinediamine compounds of the present invention are presented in Table 11. 7.18.6 The 2,4-pyrimidinediamine compounds of the present invention inhibit B-cell activation.

GF) 7.18.6.1 Description

The ability of the 2,4-pyrimidinediamine compounds of the present invention to inhibit B-cell activation has been demonstrated using primary B-cells in the analysis of cell surface markers, using fluorescent label cell sorting (HAS5). Inhibition of primary B cell activation in response to B cell receptor (BCR) stimulation was measured by quantitative analysis of the cell surface marker СОб69. 7.18.6.2 Removal of primary B cells

Primary human B-cells were isolated from the leukocyte film, which is a layer of leukocytes that forms between erythrocytes and platelets during centrifugation of non-clotting blood; or from fresh blood with the use of CO19-Yubup microspheres! 9 and sorter BAS5. The leukocyte film was obtained from the Blood Bank

Stanford University Medical Center, which was produced on the same day, stored and transported refrigerated (on ice). The leukocyte film (approximately 35 ml) was placed in a conical sterile centrifuge plate with a capacity of 50 Oml and cooled on ice, then diluted with cold phosphate-buffered saline containing 0.295 bovine serum albumin (supplier Zidt, catalog Mo A7b638) and sodium citrate (0.195, supplier Bidta, catalog No. 5-5570) (Р-В-С) to a total volume of 200 ml and carefully mixed. Fresh blood was obtained from donors in vacuum tubes with a capacity of 1 Oml containing heparin (1 vacuum tube contains approximately 8.5 ml of blood). The blood was cooled on ice, transferred to tubes with a capacity of 5Oml (2Oml/tube) or a conical sterile centrifuge tablet with a capacity of 5O0Oml, and diluted with an equal volume of R-B-C. 70 25 ml of diluted blood or leukocyte film was layered on 15 ml of cold Ficol and placed again on ice. The blood, layered on Ficoll, was centrifuged (VesKtap model (z5-6K) for 45 minutes at 2000 rpm at 42C to separate peripheral blood mononuclear cells (PBMC) from erythrocytes (red blood cells-KVS) and granulocytes. The upper aqueous layer was suctioned using an aspirator to a level of 1 inch (25.4 mm) above the PBMO layer. After that, the PBMC cells were transferred from every 2 Ficoll tubes to a clean 50ml 7/5 Raisop tube (approximately 1Oml/tube). The transferred PBMC were diluted in 5 multiple proportions of ice-cold phosphate-buffered saline with 0.296 bovine serum albumin (B-S) and centrifuged for 20 minutes at 1400 rpm at 42. Then the supernatant (may have an opaque appearance) was aspirated and the PBMC cells were resuspended in 25 ml of P -B, and cells were counted (by 1:5 dilution) and stored on ice.20 Positive cell isolation was then performed using antibody-coated magnetic microspheres and to anti-CO 19 (OupaF) according to the manufacturer's instructions. The approximate required number of microspheres was calculated

COr19-Bbupayu (microsphere M-450 (rarB) coated with CO 19, supplier Yuupakyu), assuming that the amount

B cells is 595 from the PBMCs counted and adding approximately 10 microspheres per cell from a microsphere container containing 4x10Zmicrospheres/ml. CO19-Oupaku micro spheres were washed twice with CM 25 R-B solution in a ml tube using an Oupa!F magnet, then added to the cell suspension by

RVMS. Then the mixture was passed through a magnet OSupa (Ff) and washed several times to isolate the cells bound to the microspheres. 7.18.6.3 Examination of compounds for the ability to inhibit B-cell activation

After isolation of cells, microspheres and antibodies were extracted using the (Che) 30 Vupaf CO19-OETASNavEAYUYA system for 45 minutes at 302. As a result, approximately 2x107 b

B-cells on the leukocyte film. B-cells were washed and resuspended at a concentration of 1x1 cells/ml in KRMI1640 medium with the addition of 1095 fetal calf serum, penicillin/streptadvin, and ng/ml h-

IRMo, 8. The cells were left overnight at 372С and 595С. with

The next day, the cells were washed and resuspended in KMRI medium supplemented with 2.590

From embryonic calf serum to a concentration of 1X10 bcells/ml. The cells were then introduced into a deep-bottom 9b-well plate (supplier of Sogpipe), distributing bbml of cells into each well. Using an automatic device, bbmcl 2x compounds were added to the cells to a final OM5BO concentration of 0.295, and incubated for one hour at 372C. Then the cells were stimulated with 2 μm of 7.5 μm of immunoglobulin from the company "

Vaskup Iarogaigiez (final concentration mcg/ml) within 24 hours. On the third day, 70 cells were centrifuged, stained for СОб69, and analyzed using RASZ by gating on live cells (light scattering). c We compared different concentrations of the test compounds with the solvent and established the IC value, which characterizes the ability of each compound to inhibit B-cell activation. Representative IC values for the 2,4-pyrimidinediamine compounds of this invention are presented in Table 11. 7.18.7 The 2,4-pyrimidinediamine compounds of this invention inhibit the activation of macrophages with 7.18.7.1 Description

Kz The ability of the 2,4-pyrimidinediamine compounds of this invention to inhibit the activation of -3 differentiated macrophages was demonstrated by measuring the release of cytokines by stimulated macrophages. The release of tumor necrosis factor alpha (TME) and se 50 interleukin 6 (II--6) in response to stimulation of dos or I P5 was quantified. 7.18.7.2 Purification and culture of human macrophages and Cp14-immunocytes were purified from PBMC (supplier AIiIseiz, catalog Mo РВОО2) using a kit for removal of monocytes (supplier Minepui Rioyes, catalog Mo130-045-501) in accordance with the manufacturer's instructions. The degree of purity was assessed by measuring the concentration of CO14 cells using flow cytometry. As a rule, the degree of purity was more than 9095. Purified CO1T4 cells were introduced into tablets

GF) (bl1ob cells in a 150 cm diameter Petri dish in 15 ml medium) in macrophage serum-free medium (supplier Sirso, catalog Mo12065-074) with 100 ng/ml macrophage colony-stimulating factor (supplier Rergo Tesi, catalog Mo300-25) and left to differentiate for n seven days At the end of this period, cell morphology and cell surface markers (2014, NI A-OK, 87.1, 87.2, СОб4,

СО32, and СО 16) reflected the presence of mature differentiated macrophages. 7.18.7.3 Stimulation with DO immunoglobulin

In 96-well plates Ittiop 4NVH (supplier MUK, catalog Mob2402-959) human Id obtained from the bank of human immunoglobulins (supplier Askwap Ittipogezeagsy ab, catalog 65 Me009-000-003) was introduced at a concentration of 1 Ωkg/well overnight at 42С or during 1 hour at 372C. A negative control containing the E(ab)2 fragment was also included to assess background stimulation. Unbound antibodies were washed twice with 200 ml of phosphate-buffered saline. 20 μl of 5X compound was added to each well, followed by the addition of 15,000 cells of differentiated macrophages in 8 μl, which were collected from the tablets.

The cells were incubated for 16 hours at 372C, and the supernatant was collected for further analysis of I stipeh for 1-6 and TME-alpha, which was carried out similarly to the above method for primary T cells. 7.18.7.4 Stimulation P5

For stimulation using I RB5, 1 μl of a tenfold solution was added to the pre-incubated mixture of cells/compound to a final concentration of 1 TOng/ml. Then the cells were incubated for 16 hours at 372C and the supernatants were analyzed according to the above method.

A comparison of different concentrations of compounds with the solvent was carried out and the IC 5o parameter of each compound was established for each cytokine. Representative IC values for the 2,4-pyrimidinediamine compounds of this invention are presented in Table 11.

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OO ryakh 01000110. du pt oolp OO with --------- o shi

SD ss vysh vysh p oo o V V PO

Although the above invention has been described in detail for ease of understanding, it is obvious that certain changes and modifications are possible within the framework of the appended claims. Accordingly, the described examples of implementation of the invention should be considered illustrative and not restrictive, and the present invention is not limited to the details given therein, but can be modified within the framework and in accordance with the equivalents of the appended claims.

All literature and patent sources cited in the valid application are incorporated herein by reference for all possible purposes.

Claims (1)

The formula of the invention 1. Use of a 2,4-pyrimidinediamine compound represented by the structural formula (I) for the preparation of a medicament 70 for the treatment of an autoimmune disease other than ulcerative colitis, inflammatory bowel disease, and idiopathic inflammatory bowel disease and Crohn's disease, wherein the compound 2,4 -pyrimidinediamine is: a compound of the structural formula (1): ve ve y y 2 1 vek en shk y y () or its salt, hydrate, solvate and/or M-oxide, where: I" and I? each - a direct compound "bond; B" is selected from the group containing phenyl monosubstituted in the 3- or 5-position by a KZ group, phenyl di- or trisubstituted by one or more identical or different KZ groups, and 5-15-membered heteroaryl, arbitrarily substituted by one or several identical or different groups 8; si B" is selected from the group containing phenyl, substituted by one or several identical or different groups about E8, and 5-15-membered heteroaryl, arbitrarily substituted by one or several identical or different groups 8; IN? is selected from the group containing -CM, -MS, -MO 5, fluorine, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, haloalkyl, (C1-C3) perhaloalkyl, -C(O)K2, -C (O)ОК2, -(О)СЕ" and -С(ООСЕ"; 2? represents hydrogen; и-о З is selected from the group consisting of B 2, ve, ve, replaced by one or more identical or Ф» different K2 or KR, -OK2, substituted by one or more identical or different K2 or K?, -B(OK2)", "- -B(MeUV2)5, "(СНо)т-в?, "СНУ, -О -(СНо)т-во, -8-(СНо)т в», -0-СНБев?, -о-сКУвУ, -О-(СНе)-е, -0-(СнНозСН(СН оз ЗЕ, -8 -(СНЕ2)-В, -СЩЦС(ОМН-(СНо)т-ве, -СК(ОМнА(СНАг) АК, с -0-(СН.) п С(О)МНА(СН) where, -8- (СНо)т-С(ОМНА(СНо)т-в, -о-снае)-С(ОМНА(СНе 2) во, оо -5-(СНЕ 2)4-С(О)МН-А(СНЕ 2 ) т-, -МН-(СНо)т-в, -МНА(СНЕ У) -, -МНИ(сНо) тв З, -М(СНо)ув b, -МН-С(0)-МН-(СН 2) т-в2, -МН-С(О)-(СНо)т-СНА В» and -МНА(СН»)т-С(0)-МН-(СН о)т-в; each K? independently is selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) vrylalkyl, 2-6-membered heteroalkyl, 3-8-membered 7-membered cycloheteroalkyl, 4-11-membered cycloheteroalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl; :z» each KO represents a suitable group independently selected from the group consisting of 50, -OBV 9, (C1-C3) haloidoalkyloxy, -5, -5K9, -MVU, MOVU, -MAZV2, halogen, -SEz, -SM, -MS, -"OSM, -VSM, -MO, -MO", -Mo, -M, 45. -9(0)89, -8(03589, -8(0)5089, -В(О)МА2В2, -8(02D MeV, -ОВ(ОВУ, -о8(0)589, -О8(02ОВ9 . t -os(0Ov9, -oOS(OMAsVe, -«OS(IMNMAsVe, -oOS(MKMesve, "Mne U, -mvas(olvU, -Mnesdovkae, -mves(OolOvU, MNe(oМme ve, "IMVasS(OoDMeeve, IMNeS (MnuHMe B: and (mV Cs(Me 2), MeV; - 50 each KO independently represents Kg, or, alternatively, two KOs are taken together with the nitrogen atom to which He is bound, in order to form 5-8 --len cycloheteroalkyl or heteroaryl, which may include one or more of the same or different additional heteroatoms and may be substituted by one or more of the same or different K2 or suitable VC groups; each BZ is independently a KU; each KO is independently selected from the group consisting of from (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6-ene heteroalkyl, C3-8-h- fief (F. cycloheteroalkyl, 4-11-membered cycloheteroalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl; each t independently represents an integer from 1 to 3, and 60 each n independently represents an integer from 0 to C, or the 2,4-pyrimidinediamine compound is a compound selected from the group consisting of 7.4.214 to 7.4.244, 7.4.250 to 7.4.252, 7.4.256 to 7.4.258, 7.4.262 to 7.4.269, 7.4.272 to 7.4.276, 7.4.278 to 7.4.280, 7.4.283 to 7.4.289, 7.4.296, 7.4.298 to 7.4.302, 7.4.305, 7.4.308 to 7.4.313, 7.4.315, 7.4.317 and 7.4.318; with the condition that is in formula (I) 65 (1) if K2 is substituted phenyl, then KE? does not represent cyano or -C(O)MNE, where RE. is hydrogen or (C1-C6) alkyl; (2) if 22 and B" each independently represents a substituted or unsubstituted pyrrole or indole, then B 2 and B" rings attached to another part of the molecule by means of a carbon atom; and (3) the compound is not Me. SSS OomMe o ah m me nn nn 70 5OZMNMe 2. Use according to claim 1, which differs from BC? is selected from the group consisting of 5-10-membered heteroaryl, benzodioxanyl, 1,4-benzodioxan-(5 or 6)-yl, benzodioxolyl, 1,3-benzodioxol-(4 or 5)-yl, benzoxazinyl, 1,4-benzoxazin-(5,6,7 or 8)-yl, benzoxazolyl, 1,3-benzoxazol-(4,5,6 or 7)-yl, benzopyranyl, benzopyran-(5,6,7 or 8 )-yl, benzotriazolyl, benzotriazol-(4,5,6 or 7)-yl, 759 1,4-benzoxazinyl-2-one, 1,4-benzoxazin-(5,6,7 or 8)-yl-2 -one, 2H-1,4-benzoxazinyl-3(4H)-one, 2H-1,4-benzoxazin-(5,65,7 or 8)-yl-3(4H)-one, /2H-1, 3-benzoxazinyl-2,4(ZH)-dione, /2H-1,3-benzoxazine-(5,6,7 or 8)-yl-2,4(ZH)-dione, benzoxazolyl-2-one, benzoxazole -(4,5,6 or 7)-yl-2-one, dihydrocoumarinyl, dihydrocoumarin-(5,65,7 or 8)-yl, 1,2-benzopyronyl, 1,2-benzopyrone-(5,6, 7 or 8)-yl, benzofuranyl, benzofuran-(4,5,6 or 7)-yl, benzo|p|furanyl, benzo|p|Ifuran-(4,5,6 or 7)-yl, indolyl, indole -(4,5,6 or t)-yl, pyrrolyl and pyrrol-(1 or 2)-yl, each of which may be arbitrarily substituted with one or more of the same we or different Z groups, where the EZ is defined according to claim 1. 3. Use according to claim 1, which is characterized by the fact that in it one or both 22 and 7, independently of each other, represent a selectively substituted heteroaryl selected from the group consisting of: Fri MI. pt IV : | 07-85 '| m : | kiy She y bu ila b khish u A M F nya shya M vush : | ---vo5 ! | in | i-n - P i, i s zv n A E - M more. a (c c) pe Ez5 ; . | Y)! t | ns t v bi re yet and not « 1 - h o v. o same call; "» eh Eh M o N CHA o o o p zh zolo ony '. ' ot o Z tsi a o -- 1 DY s Shd 2 bor 9 ! o (se) t | "her cut t | '. where 7 P pryak I (42) a ze 1 1 t R | t more | o more: 2-- o in o- . but yo 1 o 1 (8) Whoa! IS ; H o b5 zh ko oh ' -o , ' MOM KE: PK! PC! o I I yuo 9 or A bu i I EE htlotmo to shchi | | more and pi 0 1 she chita a And well I you and mk she NYA ' more: you і-/ I y - vyg u 1 Shen gezi s t s ia ; ' NE 11 N and U in her A ko KE su shnzhE you in 2 and 2 "se PA ya wa z (o) t | vo Shi y y chy y v" NO | m- | y se 7 Her and C rig and (ge) re ! bor bot de 7 fe Х я 5 y She: because 1 is M вх мя в) I ч шы: O live for the life! more ' t tm A | x shchi | o hm a (og) v r z" z y: dya z. Ж se du ' ! (Se) I m more: de ' r F | Y y r 5 nt and F). - ko a 60 b5 Z Eto he mo y t o he II m rya ryn Y z-d Go (8) SHV i same 9 More M kt ee -sh Y t- r Go y Z ro Z ro a (8) oh - - MN - MN х Г Г Го (8) а о с й й: о ше МН -щ МН х Й Й Го й (se) where: p is an integer from one to three; Each symbol independently represents a single or double bond; "- VZ means hydrogen or P, where B is defined according to claim 1; X is selected from the group consisting of CH, M and M-O; c each U is independently selected from the group consisting of 0, З and МН; so each U" is independently selected from the group consisting of O, 5, 50, 505, ZOM, MN and ME"; each U? independently selected from the group consisting of CH, CH», O, 5, M, MH and mA 25 means hydrogen or alkyl; "du VZ" is selected from the group consisting of hydrogen and a progroup, preferably hydrogen or a progroup selected from the group consisting of aryl, arylalkyl, heteroaryl, K 2, BR-svarve-o-c(0О88, -СВав ?-О-РО(ОВ, . -СН.-О-Ро(оК8) с(0)-СВевР-М(SNUI), -С(ОВВ, -С(О)СЕ" and "-Ф(0)-мв8-с(Ф)88; 238 is selected from the group consisting of alkyl and aryl; A is selected from the group consisting of 0, MH, and Me 38. with BZ, 8" and "7, each independently selected from the group consisting of alkyl, C 1 -C 6 alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or alternatively, BZ 87 and/or -ZB" and 87, taken together are a ketal; each 7 is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester and carbamate; (Ce) O is selected from the group consisting of "ОН, OKU, -"MEUV2, "МНЕЗ9-с(ОВ8, "МНЕ 39-с(Фов8, -МЕЗ9-СНеЕ 0-в т в, -МА39(СНо)т-в and-Me39-c(0)-СНе 70-MAevg; VZ and KO, each and independently of o bottom, are selected from the group consisting of hydrogen, alkyl, aryl, alkylaryl; arylalkyl and MNE; and 99 Va, in? Her 2: are determined by claim 1. GF! 4. Use according to item C, which differs in that 22 and B are the same. 5. Use according to paragraphs Q or 4, which is different in that each short circuit? is independently selected from the group consisting of hydrogen, K 9, -MEUV2, «СНо)т-МВУВ2, -С(О)МеВВ2, «СНо)т-С(О)Мв ev, -С(0)0К , "СНо)т-С(0ООв9 vo and -(СНо)т-ОВУ, where т, КЗ and ВУ are defined according to claim 1. 6. Use according to claim 5, which differs in that each t is equal to one. 7. Use according to claim 1, which differs in that B? means an arbitrarily substituted heteroaryl bonded to another part of the molecule by means of a carbon ring atom. 8. Use according to claim 1, which is characterized by the fact that KE" represents an arbitrarily substituted heteroaryl, connected 65 to another part of the molecule by means of a carbon ring atom. 9. Use according to claim 3, which differs in that ЕВ" represents о, and ИХ до" Н where ВЗ and ВО are determined according to clause З and further include, each independently, a hydrogen atom, and В? represents a phenyl group substituted as defined in claim 1, or yuyu | and o M u ne where B is as defined in claim 3. 10. The use according to item C, which differs in that VE represents 2 Ш! t EV5 ! У - вх where У" and У? and each В? are defined according to p. З and В? is a br | their s - shk M (о) у ne з where КЗ is defined according to claim 3. и- 11. The use according to claim 10, which differs in that U" is oxygen, U? is MH and one or more BZ parts is an (o) alkyl group. "- 12. Use according to claim 11, characterized in that the two dz attached to the same carbon atom are each methyl. with 13. The use according to claim 12, which is distinguished by the fact that ЕВ" is the compound Н 8 с 14. The use according to claim 1, which is distinguished by the fact that KE? is selected from the group consisting of fluorine, -C3) with" fluoroalkyl, (C1-C3) perfluoroalkyl, (C1-C3) fluoroalkose and (C1-C3) perfluoroalkoxy. " 15. Use according to claim 14, which differs in that KE? selected from fluorine, -CEz and -OSE". 16. Use according to claim 1, which differs in that one or both of 2 and K7 are, independently of each other, phenyl substituted with one, two or three 8 groups, where EZ is defined according to claim 1. co 17. Use according to claim 16 , which differs in that K? and 7 each identically or differently substituted with Kz phenyl. -3 18. Use according to claim 16 or 17, which is characterized in that the substituted phenyl is monosubstituted. 19. Use according to claim 18, which differs in that KE" is phenyl substituted in the ortho-, meta- or para-position. (Ce) 20. Use according to claim 18, which differs in that KZ is selected from the group that consists of (C1-C10) n alkyl, (C1-C10) branched alkyl, -OBK9U, -O-(СНо)ш-МаесВе, -ОО-С(ОМВ2, -О-(СНо)т-С(ОМАВ, -0-F(6)OkKa, -o-(SnNo)t-C(FOOV2. -O-C(MNIMEUV2, -O-(СНо)т-С(МНИМе 282, -МНА(СНо)т-МвеВг, -МН-С(О)Ме svo and -МНА(СНо)t-С(О)МА В, where т, КУ, 2: and КЗ are defined according to claim 1. 21. Use according to claim 16 or 17, characterized in that the substituted phenyl is disubstituted. 22. Use according to claim 21, which differs in that the E8 substituents occupy positions 2,3-; 2,4-; 2.5-; 2,6-; F) 3,4- or 3,5-. ko 23. Use according to claim 21, which differs in that each BU is independently selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, -OK2, arbitrarily substituted by one or more identical or different CC? or B? groups, -O-(СНо)п-MeОВ, -О-С(О)МАВ2, -О-(СНо)т-С(ОМеВг, -Оо-ск(ФфОокае, -О-(СНо)тС(ООК2, -О-С(МНИМАУКг, -0О-(СНо)зС(МНИМА Kg, -МНА«СНо)t-МКеве, -МНА-С(О)МКеКе and -МНА(СНо)t-С(О)МА В, where t, KU, 2, and 2 are defined according to claim 1. 24. Use according to claim 16 or 17, characterized in that the substituted phenyl is trisubstituted. 65 25. Use according to claim 24, which differs in that the substitutes 28 occupy positions 2,3,4; 2,3,5; 2,3,6; 2,4,5; 2,4,6; 2,5,6 or 3,45. 26. Use according to claim 25, which differs in that each BU is independently selected from the group consisting of (C1-C10) alkyl, (C1-C10) branched alkyl, -OK2, arbitrarily substituted by one or more identical or different BC? or BC? groups, -O-(СНо)ш-МесВе, -О-С(ОМАВ2, -О-(СНо)т-С(ОМА В, -0-(Фове, -О-С(МН)Магве, -ОО- (СНо)т С(ООа. -О-(СНо)п-С(МНМА ев, -МН-(СНо)l-МАУвг, -МН-С(О)МАове and -"МНА(СНо)т-С( O) MA B, where t, KU, E? and KZ are defined according to claim 1. 27. The use according to claim 24, which differs in that the trisubstituted phenyl corresponds to the following formula: 1 3 - where: VU means methyl or (C1-Cb) alkyl; B? means hydrogen, methyl or (C1-Cb) alkyl; and VZ means a halogen group. 28. Use according to claim 17, which differs in that 22 and 27 are the same. ух 29. Use according to claim 1, where the 2,4-pyrimidinediamine compound corresponds to the following structural formula (IB): ве в! wow! ry ovo You M I M you s n n ; or a salt, hydrate, solvate and/or M-oxide thereof, characterized in that B" and B"M are each independently selected from the group consisting of hydroxy, (C1-C6) alkoxy and -ME 92; B" and B"Z are each hydrogen; and E? and 2? defined according to claim 1. "o 30. Use according to claim 1, in which the 2,4-pyrimidinediamine compound corresponds to the following structural formula (Is): ге ЧО Ф я 2-4 "-- чеше МОМ в с Н нн со or its salts, hydrate, solvate and/or M-oxide, which differs in that Ge represents phenyl, arbitrarily substituted from 1 to 3 with the same or different EZ groups or a 5-14-membered heteroaryl, arbitrarily substituted from 1 to 4 with the same or different З groups; "WHAT? and the short circuit are as defined in claim 1; and 70 B" is -O(CHNo)t-Be, where t and KE? are as defined in claim 1. With p. 31. Use according to claim 30, characterized in that KE" is an arbitrarily substituted heteroaryl. from 32. The use according to claim 30, which differs in that the short circuit is О-СНо-С(0)-МНОН 3. 33. Use according to claim 1, which is characterized by the fact that the 2,4 pyrimidinediamine compound is selected from the group consisting of the following compounds: ), M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-I3-(M-methylamino)carbonylmethyleneoxy|phenyl/|-2,4-pyrimidinediamine ko (K926891), - m4-(2,2 -dimethyl-4H-benzo|1,oxazin-3-mono)-6-yl|-5-fluoro-H2-IZ-(methylaminocarbonylmethyleneoxy)phenyl|-2, 4-pyrimidinediamine (K940323), (Се) m4-( 2,2-dimethyl-4H-5-pyrido|1,Doxazin-3-mono)-6-yl|-5-fluoro-M2-IZ-«(methylaminocarbonylmethyleneoxy)phenyl Pho -2,4-pyrimidinediamine (KU40347) and m4-(2,2-difluoro-4H-benzo|1,oxazin-3-mono)-6-yl|-5-fluoro-M2-III-"methylaminocarbonylmethyleneoxy)phenyl/d-2,4-pyrimidinediamine (K921303) . 34. Use according to claim 1, which is characterized by the fact that the 2,4-pyrimidinediamine compound is selected from the group consisting of compounds 7.4.30 to 7.4.090, 7.4.101 to 7.4.138, 7.4.147 to 7.4.150, 7.4.152 to 7.4.180, 7.4.183, (F) 7.4.186, 7.4.187, 7.4.194 to 7.4.211, 7.4.213, 7.4.245, 7.4.247 to 7.4.249, 7.4.253 to 7.4.255, 7.4.259 to t 7.4.261, 7.4.270, 7.4.271, 7.4.277, 7.4.281, 7.4.282, 7.4.290 to 7.4.295, 7.4.297, 7.4.303, 7.4.306, 7.4.307, 7.4.314, 7.4.316, 7.4.319 to 7.4.329, 7.4.342 to 7.4.362, 7.4.372 to 7.4.382 and 7.4.384 to 7.4.445. in 35. Use according to claim 1, which differs in that the 2,4-pyrimidinediamine compound is: 5(5)-5-fluoro-M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl|-M4-(2-methyl- 3-oxo-4H-benzyl|1, Doxazin-6-yl)-2, 4-pyrimidinediamine (K909317); (K)-5-fluoro-M2-I3-(M-methylamino)carbonylmethyleneoxyphenyl/|-M4-(2-methyl-3-oxo-4H-benz(|1,Doxazin-6-yl)-2,4 - pyrimidinediamine (K909317); 65 m4-(2,2-difluoro-3-oxo-4H-benz(|1,oxazin-6-yl)-M2-(3,5-dimethyloxyphenyl)-5-fluoro-2,4 -pyrimidinediamine (K926970); M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2-difluoro-3-oxo-4H-benz|1,oxazin-6-yl)-5-fluoro-2,4- pyrimidine amine (KU26971); M2-(3,5-dichloro-4-hydroxyphenyl)-M4-(2,2-difluoro-3-oxo-4H-benz|1,oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine ( K927048); M2-(3,5-dichloro-4-hydroxyphenyl)-M4-(2,2-dimethyl-3-oxo-4H-benzyl|1,oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine (K927051); M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2-dimethyl-3-oxo-4H-benz(|1,4oxazin-6-yl)-5-fluoro-2, 4-pyrimidine amine (K940358); 70 M2-(3-chloro-4-methoxy-5-methylphenyl)-M4-(2,2-dimethyl-3-oxo-4H-benz(|1,4oxazin-6-yl )-5-fluoro-2,4-pyrimidinediamine (K940358); m4-(2,2-dimethyl-3-oxo-4H-benz(|1,oxazin-6-yl)-5-fluoro-M2-( indazolin-b-yl)-2,4-pyrimidinediamine (K940363); m4-(2,2-dimethyl-3-oxo-4H-benz|1,oxazin-6-yl)-5-fluoro-M2-(M4 -methylindazolin-b-yl)-2,4-pyrimidinediamine (K940366); m4-(2,2-difluoro-3-oxo-4H-benz(|1,4oxazin-6-yl)-5-fluoro-M2- (1-methylindazolin-6-yl)-2,4-pyrimidinediamine (K940368) or M2-(3,5-dimethoxyphenyl)-5-fluoro-M4-(2H-3-oxo-4H-5-pyridi(1, Zoxazin-6-yl)-2,4-pyrimidinediamine (K945401). 36. Use according to claim 1, which differs in that the 2,4-pyrimidinediamine compound is: m4-(3,3-dimethyl-4H-benzyl)-5-fluoro-M2-( M1-methylindazol-b-yl)-2,4-pyrimidinediamine (908592); m4-(2,2-dimethyl-3-oxo-4H-benz|1,oxazin-6-yl)-5-fluoro-M2-|(1-(3-hydroxypropyl)indazolin-5-yl)-2, 4-pyrimidindiamine (K935432); M4-(3-chloro-4-methoxyphenyl)-5-fluoro-M2-(1-(3-hydroxypropyl)indazolin-5-yl)-2,4-pyrimidinediamine (K935461); m4-(2,2-difluoro-3-oxo-4H-benz(|1,oxazin-6-yl)-5-fluoro-M2-(indazolin-b-yl)-2,4-pyrimidinediamine (K940364); M4-(2,2-dimethyl-3-oxo-4H-5-pyrid/(1,Zoxazin-6-yl)-5-fluoro-M2-(indazolin-b-yl)-2,4-pyrimidinediamine (K940380 ); c M2-(3-chloro-4-hydroxy-5-methylphenyl)-M4-(2,2-dimethyl-3-oxo-4H-5-pyridyl1,4|-oxazin-6-yl)-5- fluoro-2,4-pyrimidindiamine (K940394); (8) M2-(3,5-dimethyl-4-methoxyphenyl)-M4-(2,2-dimethyl-3-oxo-4H-5-pyride)/1 ,41-oxazin-b-yl)-5-fluoro-2,4-pyrimidinediamine (K940395) or M4-(4-amino-1-benzopyran-6b-yl)-5-fluoro-M2-(indazol-b -yl)-2,4-pyrimidinediamine (K950423). 37. Use according to any of claims 1-36, which is characterized by the fact that the drug is used in the form of a pharmaceutical composition, which includes the compound and a pharmaceutically acceptable carrier, solvent and excipient. b" 38. Use according to any of claims 1-36, characterized in that the autoimmune disease is selected from the group consisting of "- autoimmune diseases, often defined as autoimmune disorders and autoimmune diseases of one organ or one cell type, which often are defined as a systemic autoimmune disorder caused by disease co 39. Use according to claim 38, characterized in that the autoimmune disease is selected from the group consisting of: autoimmune thyroiditis (Hashimoto's disease), autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture syndrome, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Bazedov's disease, primary biliary cirrhosis, « 70 Chronic aggressive hepatitis and membranous glomerulopathy. - p 40. Use according to claim 38, which is characterized by the fact that the autoimmune disease is selected from the group consisting of the following: systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis, dermatomyositis, systemic sclerosis, polyarteritis nodosa, diffuse sclerosis and bullous pemphigoid. 41. Use according to claim 40, which differs in that the autoimmune disease is systemic lupus erythematosus. 42. Use according to claim 40, characterized in that the autoimmune disease is rheumatoid arthritis. - 43. Use according to claim 40, which differs in that the autoimmune disease is multiple sclerosis. se) 44. The use according to claim 1, which differs in that the 2,4-pyrimidinediamine compound is Fo m4-K(2,2-difluoro-4H-benzoyl|1,oxazin-3-one)-6-yl| -5-fluoro-M2-(3-(methylaminocarbonylmethyleneoxy)phenyl|)-2,4-pyrimidinediamine (K921303). 45. Use according to claim 1, which differs in that the autoimmune disease is glomerulonephritis F) ko 60 b5